Comparative evaluation of polymeric and amphiphilic cyclodextrin nanoparticles for effective camptothecin delivery.

PubMed

Cirpanli, Yasemin; Bilensoy, Erem; Lale Doğan, A; Caliş, Sema

2009-09-01

Camptothecin (CPT) is a potent anticancer agent. The clinical application of CPT is restricted by poor water solubility and instability under physiological conditions. Solubilization and stabilization of CPT were realized through nanoparticulate systems of amphiphilic cyclodextrins, poly(lactide-co-glycolide) (PLGA) or poly-epsilon-caprolactone (PCL). Nanoparticles were prepared with nanoprecipitation technique, whereas cyclodextrin nanoparticles were prepared from preformed inclusion complexes of CPT with amphiphilic cyclodextrins. Polymeric nanoparticles, on the other hand, were loaded with CPT:HP-beta-CD inclusion complex to solubilize and stabilize the drug. Mean particle sizes were under 275 nm, and polydispersity indices were lower than 0.2 for all formulations. Drug-loading values were significantly higher for amphiphilic cyclodextrin nanoparticles when compared with those for PLGA and PCL nanoparticles. Nanoparticle formulations showed a significant controlled release profile extended up to 12 days for amphiphilic cyclodextrin nanoparticles and 48h for polymeric nanoparticles. Anticancer efficacy of the nanoparticles was evaluated in comparison with CPT solution in dimethyl sulfoxide (DMSO) on MCF-7 breast adenocarcinoma cells. Amphiphilic cyclodextrin nanoparticles showed higher anticancer efficacy than PLGA or PCL nanoparticles loaded with CPT and the CPT solution in DMSO. These results indicated that CPT-loaded amphiphilic cyclodextrin nanoparticles might provide a promising carrier system for the effective delivery of this anticancer drug having bioavailability problems.

Camptothecin prodrug nanomicelle based on a boronate ester-linked diblock copolymer as the carrier of doxorubicin with enhanced cellular uptake.

PubMed

Gao, Ya; Xiao, Yi; Liu, Shiyuan; Yu, Jiahui

2018-02-01

A novel pH-sensitive polymeric prodrug of camptothecin (CPT) by polymerizing γ-camptothecin-glutamate N-carboxyanhydride (Glu (CPT)-NCA) on boronate ester-linked poly (ethyleneglycol) (PEG) directly via the amine-initiated ring open polymerization (ROP) has been developed. The resulting amphiphilic prodrug (mPEG-BC-PGluCPT) could self-assemble into nanoparticles and encapsulate doxorubicin (Dox) simultaneously in aqueous solution for dual-drug delivery. The formation of polymeric prodrug micelles (mPEG-BC@PGluCPT) was confirmed by the measurements of critical aggregation concentration (CAC), particle size, and morphology observations. The mPEG-BC@PGluCPT micelles were colloidally stable in solutions for two weeks. Polymeric prodrug micelles mPEG-BC@PGluCPT and Dox-loaded micelles mPEG-BC@PGluCPT⋅Dox showed sustained drug release profiles over 48 h. As expected, drug release was accelerated by the decreasement of pH value from 7.4 to 6.0, which demonstrated pH-dependent manner of drug release. Additionally, it was found that cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles on HepG2 cells was higher than that on HL-7702 cells, especially in culture medium at pH 6.0. The enhanced cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles under acidic condition on HepG2 cells resulted in the higher cytotoxicity of mPEG-BC@PGluCPT⋅Dox micelles at acidic pH than that at pH 7.4.

Noxa/Mcl-1 Balance Regulates Susceptibility of Cells to Camptothecin-Induced Apoptosis1

PubMed Central

Mei, Yide; Xie, Chongwei; Xie, Wei; Tian, Xu; Li, Mei; Wu, Mian

2007-01-01

Although camptothecin (CPT) has been reported to induce apoptosis in various cancer cells, the molecular details of this regulation remain largely unknown. In this study, we demonstrate that BH3-only protein Noxa is upregulated during CPT-induced apoptosis, which is independent of p53. In addition, we show that phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay and cAMP response element binding protein (CREB) knockdown experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. Moreover, blocking Noxa expression using specific small interfering ribonucleic acid (siRNA) significantly reduces the apoptosis in response to CPT, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, antiapoptotic Mcl-1 was also upregulated through PI3K/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, Noxa was found to interact with Mcl-1 in the presence or absence of CPT. Knockdown of Mcl-1 expression by short hairpin ribonucleic acid (shRNA) was shown to potentiate CPT-induced apoptosis. Consistently, ectopic overexpression of Mcl-1 rescued cells from apoptosis induced by CPT. Cells coexpressing Noxa and Mcl-1 at different ratio correlates well with the extent of apoptosis, suggesting that the balance between Noxa and Mcl-1 may determine the susceptibility of HeLa cells to CPT-induced apoptosis. PMID:17971907

Preparation of a mesoporous silica-based nano-vehicle for dual DOX/CPT pH-triggered delivery.

PubMed

Llinàs, Maria C; Martínez-Edo, Gabriel; Cascante, Anna; Porcar, Irene; Borrós, Salvador; Sánchez-García, David

2018-11-01

A dual doxorubicin/camptothecin (DOX/CPT) pH-triggered drug delivery mesoporous silica nanoparticle (MSN)-based nano-vehicle has been prepared. In this drug-delivery system (DDS), CPT is loaded inside the pores of the MSNs, while DOX is covalently attached to the surface of an aldehyde-functionalized MSN through a dihydrazide-polyethylene glycol chain. Thus, DOX and the linker act as pH-sensitive gatekeeper. The system is versatile and easy to assemble, not requiring the chemical modification of the drugs. While at physiological conditions the release of the drugs is negligible, at acidic pH a burst release of DOX and a gradual release of CPT take place. In vitro cytotoxicity tests have demonstrated that this DDS can deliver efficiently DOX and CPT for combination therapy.

hMSH5 Facilitates the Repair of Camptothecin-induced Double-strand Breaks through an Interaction with FANCJ*

PubMed Central

Xu, Yang; Wu, Xiling; Her, Chengtao

2015-01-01

Replication stress from stalled or collapsed replication forks is a major challenge to genomic integrity. The anticancer agent camptothecin (CPT) is a DNA topoisomerase I inhibitor that causes fork collapse and double-strand breaks amid DNA replication. Here we report that hMSH5 promotes cell survival in response to CPT-induced DNA damage. Cells deficient in hMSH5 show elevated CPT-induced γ-H2AX and RPA2 foci with concomitant reduction of Rad51 foci, indicative of impaired homologous recombination. In addition, CPT-treated hMSH5-deficient cells exhibit aberrant activation of Chk1 and Chk2 kinases and therefore abnormal cell cycle progression. Furthermore, the hMSH5-FANCJ chromatin recruitment underlies the effects of hMSH5 on homologous recombination and Chk1 activation. Intriguingly, FANCJ depletion desensitizes hMSH5-deficient cells to CPT-elicited cell killing. Collectively, our data point to the existence of a functional interplay between hMSH5 and FANCJ in double-strand break repair induced by replication stress. PMID:26055704

Ultrasound-responsive nanobubbles contained with peptide-camptothecin conjugates for targeted drug delivery.

PubMed

Xie, Xiangyang; Lin, Wen; Liu, Hui; Deng, Jianping; Chen, Ying; Liu, Hong; Fu, Xudong; Yang, Yang

2016-10-01

To improve the targeting delivery efficiency of anticancer drug to tumor sites, a new strategy combining cell-permeable peptide (CPP) and ultrasound was reported in this article. In this study, we devised and tested a strategy for functional payload delivery to cells by loading CPP-camptothecin conjugate (CPP-CPT) into nanobubble (CPP-CPT NB). Here, CPP existing in the conjugation form of CPP and CPT was hidden in nanobubble to cloak the penetration activity of CPP. Meanwhile, local tumor ultrasound was utilized to achieve specific targeting of CPP-CPT to the tumor cells. The mean particle size of the prepared CPP-CPT NB was ∼200 nm, and the drug entrapment efficiency was >80%. Stimulated by ultrasound, over 90% of the entrapped CPP-CPTs would release from the nanobubbles. Subsequent research demonstrated that the CPP-CPT NB showed effective cellular uptake and significant cytotoxic activity in HeLa cells in vitro. Additionally, after systemic administration in mice, CPP-CPT NB with ultrasound showed a higher tumor inhibition effect in nude mice xenografted HeLa cells tumors and excellent body safety when compared with normal CPT injection group. In conclusion, the carrier constructed in this study would be a safe and efficiently drug delivery system for specific cancer treatment.

Protein arginine (N)-methyl transferase 7 (PRMT7) as a potential target for the sensitization of tumor cells to camptothecins.

PubMed

Verbiest, Vincent; Montaudon, Danièle; Tautu, Michel T; Moukarzel, Joyce; Portail, Jean-Pierre; Markovits, Judith; Robert, Jacques; Ichas, François; Pourquier, Philippe

2008-04-30

PRMT7 belongs to the protein arginine methyl-transferases family. We show that downregulation of PRMT7alpha and beta isoforms in DC-3F hamster cells was associated with increased sensitivity to the Top1 inhibitor camptothecin (CPT). This effect was not due to a change in Top1 contents or catalytic activity, or to a difference in the reversal of DNA breaks. Overexpression of PRMT7alpha and beta in DC-3F cells had no effect on CPT sensitivity, whereas it conferred a resistance to DC-3F/9-OH-E cells for which both isoforms are reduced by two- to three-fold as compared to DC-3F parental cells. Finally, downregulation of the human PRMT7 could also sensitize HeLa cells to CPT, suggesting that it could be used as a target to potentiate CPT derivatives.

Hydrophobically modified glycol chitosan nanoparticles-encapsulated camptothecin enhance the drug stability and tumor targeting in cancer therapy.

PubMed

Min, Kyung Hyun; Park, Kyeongsoon; Kim, Yoo-Shin; Bae, Sang Mun; Lee, Seulki; Jo, Hyung Gon; Park, Rang-Woon; Kim, In-San; Jeong, Seo Young; Kim, Kwangmeyung; Kwon, Ick Chan

2008-05-08

To prepare a water-insoluble camptothecin (CPT) delivery carrier, hydrophobically modified glycol chitosan (HGC) nanoparticles were constructed by chemical conjugation of hydrophobic 5beta-cholanic acid moieties to the hydrophilic glycol chitosan backbone. Insoluble anticancer drug, CPT, was easily encapsulated into HGC nanoparticles by a dialysis method and the drug loading efficiency was above 80%. CPT-encapsulated HGC (CPT-HGC) nanoparticles formed nano-sized self-aggregates in aqueous media (280-330 nm in diameter) and showed sustained release of CPT for 1 week. Also, HGC nanoparticles effectively protected the active lactone ring of CPT from the hydrolysis under physiological condition, due to the encapsulation of CPT into the hydrophobic cores in the HGC nanoparticles. The CPT-HGC nanoparticles exhibited significant antitumor effects and high tumor targeting ability towards MDA-MB231 human breast cancer xenografts subcutaneously implanted in nude mice. Tumor growth was significantly inhibited after i.v. injection of CPT-HGC nanoparticles at doses of 10 mg/kg and 30 mg/kg, compared to free CPT at dose of 30 mg/kg. The significant antitumor efficacy of CPT-HGC nanoparticles was attributed to the ability of the nanoparticles to show both prolonged blood circulation and high accumulation in tumors, as confirmed by near infrared (NIR) fluorescence imaging systems. Thus, the delivery of CPT to tumor tissues at a high concentration, with the assistance of HGC nanoparticles, exerted a potent therapeutic effect. These results reveal the promising potential of HGC nanoparticles-encapsulated CPT as a stable and effective drug delivery system in cancer therapy.

Effects of camptothecin or TOP1 overexpression on genetic stability in Saccharomyces cerevisiae.

PubMed

Sloan, Roketa; Huang, Shar-Yin Naomi; Pommier, Yves; Jinks-Robertson, Sue

2017-11-01

Topoisomerase I (Top1) removes DNA torsional stress by nicking and resealing one strand of DNA, and is essential in higher eukaryotes. The enzyme is frequently overproduced in tumors and is the sole target of the chemotherapeutic drug camptothecin (CPT) and its clinical derivatives. CPT stabilizes the covalent Top1-DNA cleavage intermediate, which leads to toxic double-strand breaks (DSBs) when encountered by a replication fork. In the current study, we examined genetic instability associated with CPT treatment or with Top1 overexpression in the yeast Saccharomyces cerevisiae. Two types of instability were monitored: Top1-dependent deletions in haploid strains, which do not require processing into a DSB, and instability at the repetitive ribosomal DNA (rDNA) locus in diploid strains, which reflects DSB formation. Three 2-bp deletion hotspots were examined and mutations at each were elevated either when a wild-type strain was treated with CPT or when TOP1 was overexpressed, with the mutation frequency correlating with the level of TOP1 overexpression. Under both conditions, deletions at novel positions were enriched. rDNA stability was examined by measuring loss-of-heterozygosity and as was observed previously upon CPT treatment of a wild-type strain, Top1 overexpression destabilized rDNA. We conclude that too much, as well as too little of Top1 is detrimental to eukaryotic genomes, and that CPT has destabilizing effects that extend beyond those associated with DSB formation. Copyright © 2017 Elsevier B.V. All rights reserved.

Phenylbutyrate inhibits homologous recombination induced by camptothecin and methyl methanesulfonate.

PubMed

Kaiser, Gitte S; Germann, Susanne M; Westergaard, Tine; Lisby, Michael

2011-08-01

Homologous recombination is accompanied by extensive changes to chromatin organization at the site of DNA damage. Some of these changes are mediated through acetylation/deacetylation of histones. Here, we show that recombinational repair of DNA damage induced by the anti-cancer drug camptothecin (CPT) and the alkylating agent methyl methanesulfonate (MMS) is blocked by sodium phenylbutyrate (PBA) in the budding yeast Saccharomyces cerevisiae. In particular, PBA suppresses CPT- and MMS-induced genetic recombination as well as DNA double-strand break repair during mating-type interconversion. Treatment with PBA is accompanied by a dramatic reduction in histone H4 lysine 8 acetylation. Live cell imaging of homologous recombination proteins indicates that repair of CPT-induced DNA damage is redirected to a non-recombinogenic pathway in the presence of PBA without loss in cell viability. In contrast, the suppression of MMS-induced recombination by PBA is accompanied by a dramatic loss in cell viability. Taken together, our results demonstrate that PBA inhibits DNA damage-induced homologous recombination likely by mediating changes in chromatin acetylation. Moreover, the combination of PBA with genotoxic agents can lead to different cell fates depending on the type of DNA damage inflicted. 2011 Elsevier B.V. All rights reserved.

Camptothecin-loaded fusogenic nanodroplets as ultrasound theranostic agent in stem cell-mediated drug-delivery system.

PubMed

Ho, Yi-Ju; Chiang, Yu-Jung; Kang, Shih-Tsung; Fan, Ching-Hsiang; Yeh, Chih-Kuang

2018-05-28

Adipose-derived stem cells (ADSCs) have been utilized in cellular delivery systems to carry therapeutic agents into tumors by migration. Drug-loaded nanodroplets release drugs and form bubbles after acoustic droplet vaporization (ADV) triggered by ultrasound stimulation, providing a system for ultrasound-induced cellular delivery of theranostic agents. In order to improve the efficiency of drug release, fusogenic nanodroplets were designed to go from nano to micron size upon uptake by ADSCs for reducing ADV threshold. The purpose of our study was to demonstrate the utility of camptothecin-loaded fusogenic nanodroplets (CPT-FNDs) as ultrasound theranostic agents in an ADSCs delivery system. CPT-FNDs showed an increase in size from 81.6 ± 3.5 to 1043.5 ± 28.3 nm and improved CPT release from 22.0 ± 1.8% to 37.6 ± 2.1%, demonstrating the fusion ability of CPT-FNDs. CPT-FNDs-loaded ADSCs demonstrated a cell viability of 77 ± 4%, and the in vitro migration ability was 3.2 ± 1.2-fold for the tumor condition compared to the cell growth condition. Ultrasound enhancement imaging showed intratumoral ADV-generated bubble formation (increasing 3.24 ± 0.47 dB) triggered by ultrasound after CPT-FNDs-loaded ADSCs migration into B16F0 tumors. Histological images revealed intratumoral distribution of CPT-FNDs-loaded ADSCs and tissue damage due to the ADV. The CPT-FNDs can be used as theranostic agents in an ADSCs delivery system to provide the ultrasound contrast imaging and deliver combination therapy of drug release and physical damage after ADV. Copyright © 2018 Elsevier B.V. All rights reserved.

Biologically active quinoline and quinazoline alkaloids part I.

PubMed

Shang, Xiao-Fei; Morris-Natschke, Susan L; Liu, Ying-Qian; Guo, Xiao; Xu, Xiao-Shan; Goto, Masuo; Li, Jun-Cai; Yang, Guan-Zhou; Lee, Kuo-Hsiung

2018-05-01

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids. © 2017 Wiley Periodicals, Inc.

Camptothecine production by mixed fermentation of two endophytic fungi from Nothapodytes nimmoniana.

PubMed

Bhalkar, Bhumika N; Patil, Swapnil M; Govindwar, Sanjay P

2016-01-01

Two endophytic fungi isolated from the endangered plant Nothapodytes nimmoniana (Grah.) Mabb. were found to effectively synthesize CPT independent of their host plant under submerged fermentation conditions. Molecular characterization of fungi revealed their identity as Colletotrichum fructicola SUK1 (F1) and Corynespora cassiicola SUK2 (F2). Mixed fermentation experiments were carried out to study the effect of microbial signalling between the two fungal species on camptothecine production. Effect of culture parameters on CPT production was studied for both mono-cultures (F1 and F2) separately as well as for the mixed fermentation (F1 + F2). Further the most influencing ones were optimized statistically using response surface methodology. Statistical model based optimized parameters were whey (70 %), agitation rate (110 rpm), temperature (30 °C), and incubation period (7 d) for the mixed fermentation. Monocultures of the two fungal species F1 and F2 yielded CPT up to 33 ± 1.1 mg l(-1)and 69 ± 1.1 mg l(-1), respectively; while their mixed fermentation under the optimized conditions yielded up to 146 ± 0.2 mg l(-1). HPLC and LC-MS/MS techniques were used to analyze the products obtained. Copyright © 2016 British Mycological Society. Published by Elsevier Ltd. All rights reserved.

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

Development and validation of an HPLC method to quantify camptothecin in polymeric nanocapsule suspensions.

PubMed

Granada, Andréa; Murakami, Fabio S; Sartori, Tatiane; Lemos-Senna, Elenara; Silva, Marcos A S

2008-01-01

A simple, rapid, and sensitive reversed-phase column high-performance liquid chromatographic method was developed and validated to quantify camptothecin (CPT) in polymeric nanocapsule suspensions. The chromatographic separation was performed on a Supelcosil LC-18 column (15 cm x 4.6 mm id, 5 microm) using a mobile phase consisting of methanol-10 mM KH2PO4 (60 + 40, v/v; pH 2.8) at a flow rate of 1.0 mL/min and ultraviolet detection at 254 nm. The calibration graph was linear from 0.5 to 3.0 microg/mL with a correlation coefficient of 0.9979, and the limit of quantitation was 0.35 microg/mL. The assay recovery ranged from 97.3 to 105.0%. The intraday and interday relative standard deviation values were < 5.0%. The validation results confirmed that the developed method is specific, linear, accurate, and precise for its intended use. The current method was successfully applied to the evaluation of CPT entrapment efficiency and drug content in polymeric nanocapsule suspensions during the early stage of formulation development.

Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea.

PubMed

Takasuna, K; Hagiwara, T; Watanabe, K; Onose, S; Yoshida, S; Kumazawa, E; Nagai, E; Kamataki, T

2006-10-01

An antitumor camptothecin derivative CPT-11 has proven a broad spectrum of solid tumor malignancy, but its severe diarrhea has often limited its more widespread use. We have demonstrated from a rat model that intestinal beta-glucuronidase may play a key role in the development of CPT-11-induced delayed diarrhea by the deconjugation of the luminal SN-38 glucuronide, and the elimination of the intestinal microflora by antibiotics or dosing of TJ-14, a Kampo medicine that contains beta-glucuronidase inhibitor baicalin, exerted a protective effect. In the present study, we assessed the efficacy of several potential treatments in our rat model to clarify which is the most promising treatment for CPT-11-induced delayed diarrhea. Oral dosing (twice daily from days -1 to 4) of streptomycin 20 mg/kg and penicillin 10 mg/kg (Str/Pen), neomycin 20 mg/kg and bacitracin 10 mg/kg (Neo/Bac), both of which inhibited almost completely the fecal beta-glucuronidase activity, or TJ-14 1,000 mg/kg improved the decrease in body weight and the delayed diarrhea symptoms induced by CPT-11 (60 mg/kg i.v. from days 1 to 4) to a similar extent. The efficacy was less but significant in activated charcoal (1,000 mg/kg p.o. twice daily from days -1 to 4). In a separate experiment using rats bearing breast cancer (Walker 256-TC), TJ-14, Neo/Bac, and charcoal at the same dose regimen improved CPT-11-induced intestinal toxicity without reducing CPT-11's antitumor activity. In contrast, oral dosing (twice a day) of cyclosporin A (50 mg/kg), a P-glycoprotein and cMOAT/MRP2 inhibitor or valproic acid (200 mg/kg), a UDP-glucuronosyltranferase inhibitor, exacerbated the intestinal toxicity without modifying CPT-11's antitumor activity. The result clearly demonstrated the ability of Neo/Bac, Str/Pen, and TJ-14, less but significant ability of activated charcoal, to ameliorate CPT-11-induced delayed-onset diarrhea, suggesting the treatments decreasing the exposure of the intestines to the luminal SN-38

Camptothecin Attenuates Cytochrome P450 3A4 Induction by Blocking the Activation of Human Pregnane X ReceptorS⃞

PubMed Central

Chen, Yakun; Tang, Yong; Robbins, Gregory T.

2010-01-01

Differential regulation of drug-metabolizing enzymes (DMEs) is a common cause of adverse drug effects in cancer therapy. Due to the extremely important role of cytochrome P450 3A4 (CYP3A4) in drug metabolism and the dominant regulation of human pregnane X receptor (hPXR) on CYP3A4, finding inhibitors for hPXR could provide a unique tool to control drug efficacies in cancer therapy. Camptothecin (CPT) was demonstrated as a novel and potent inhibitor (IC50 = 0.58 μM) of an hPXR-mediated transcriptional regulation on CYP3A4 in this study. In contrast, one of its analogs, irinotecan (CPT-11), was found to be an hPXR agonist in the same tests. CPT disrupted the interaction of hPXR with steroid receptor coactivator-1 but had effects on neither the competition of ligand binding nor the formation of the hPXR and retinoid X receptor α heterodimer, nor the interaction between the regulatory complex and DNA-responsive elements. CPT treatment resulted in delayed metabolism of nifedipine in human hepatocytes treated with rifampicin, suggesting a potential prevention of drug-drug interactions between CYP3A4 inducers and CYP3A4-metabolized drugs. Because CPT is the leading compound of topoisomerase I inhibitors, which comprise a quickly developing class of anticancer agents, the findings indicate the potential of a new class of compounds to modify hPXR activity as agonists/inhibitors and are important in the development of CPT analogs. PMID:20504912

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

Novel 20(S)-sulfonylamidine derivatives of camptothecin and the use thereof as a potent antitumor agent: a patent evaluation of WO2015048365 (A1).

PubMed

Beretta, Giovanni Luca; Zaffaroni, Nadia; Varchi, Greta

2016-05-01

A series of camptothecin (CPT) derivatives featuring acyl-esterification of the 20(S)-hydroxyl group with a residue containing a sulfonylamidine moiety is synthesized via a Cu catalyzed three-component reaction. The compounds show remarkable cytotoxicity against a panel of tumor cells, including a cell line exhibiting Multi-Drug Resistant (MDR) phenotype. The patent develops 9a, the best derivative of the series, that i) selectively poisons DNA Topoisomerase I (TopoI); ii) induces cell-cycle S-phase arrest with activation of the DNA damage response pathway and apoptosis induction and iii) shows considerable in vivo antitumor potency. We envision that the peculiar modification of the 20(S)-hydroxyl group of CPT with a sulfonylamidine residue will play a continuing role in affording new TopoI poison drug candidates for therapeutic applications.

Development and evaluation of camptothecin loaded polymer stabilized nanoemulsion: Targeting potential in 4T1-breast tumour xenograft model.

PubMed

Sugumaran, Abimanyu; Ponnusamy, Chandrasekar; Kandasamy, Palanivel; Krishnaswami, Venkateshwaran; Palanichamy, Rajaguru; Kandasamy, Ruckmani; Lakshmanan, Manikandan; Natesan, Subramanian

2018-04-30

Targeted delivery of anticancer agents is poised to improve cancer therapy, for which polymers can serve as targeting ligands or nanocarriers for chemotherapeutic agents. In this study, we have developed and evaluated the efficacy of a camptothecin (CPT)-loaded polymer stabilized nanoemulsion (PSNE) for the passive targeted delivery to breast cancer. Based on the pseudo-ternary phase diagrams, PSNEs were developed using capmul MCM:poloxamer 407 (4:1), solutol HS 15:simulsol P23 (1:2) and water. CPT polymer mixture was developed by solvent evaporation technique. The PSNEs were characterized for droplet size distribution, plasma protein adsorption, drug release, in-vivo targeting potential, hemolytic potential, cytotoxicity, genotoxicity, in-vivo biodistribution and CPT lactone ring stability. The developed PSNEs showed uniform droplet distribution, extended drug release (76.59±6.12% at 24h), acceptable hemolytic potential, significant cytotoxicity (IC 50 =176±4.3ng/mL) and genotoxicity against MCF-7 cancer cells but low DNA damage potential in human peripheral blood lymphocytes. The efficiency of PSNEs for the targeted delivery of CPT into the tumour regions was documented in 4T1-breast tumour xenografted BALB/c mice. In-vivo biodistribution study shows that 7105.84±568.46ng/g of CPT was passively targeted from PSNE to breast cancer tissue. About 80% of the lactone form was stable for 24h. Taken together, our study provides a promising strategy for developing PSNE-targeted drug delivery system for the breast cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38.

PubMed

Bala, Vaskor; Rao, Shasha; Boyd, Ben J; Prestidge, Clive A

2013-11-28

SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines. © 2013 Elsevier B.V. All rights reserved.

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.

Role of the protein in the DNA sequence specificity of the cleavage site stabilized by the camptothecin topoisomerase IB inhibitor: a metadynamics study

PubMed Central

Coletta, Andrea; Desideri, Alessandro

2013-01-01

Camptothecin (CPT) is a topoisomerase IB (TopIB) selective inhibitor whose derivatives are currently used in cancer therapy. TopIB cleaves DNA at any sequence, but in the presence of CPT the only stabilized protein–DNA covalent complex is the one having a thymine in position −1 with respect to the cleavage site. A metadynamics simulation of two TopIB–DNA–CPT ternary complexes differing for the presence of a thymine or a cytosine in position −1 indicates the occurrence of two different drug’s unbinding pathways. The free-energy difference between the bound state and the transition state is large when a thymine is present in position −1 and is strongly reduced in presence of a cytosine, in line with the different drug stabilization properties of the two systems. Such a difference is strictly related to the changes in the hydrogen bond network between the protein, the DNA and the drug in the two systems, indicating a direct role of the protein in determining the specificity of the cleavage site sequence stabilized by the CPT. Calculations carried out in presence of one compound of the indenoisoquinoline family (NSC314622) indicate a comparable energy difference between the bound and the transition state independently of the presence of a thymine or a cytosine in position −1, in line with the experimental results. PMID:24003027

Synthesis of an immunoconjugate of camptothecin.

PubMed

Walker, Michael A; Dubowchik, Gene M; Hofstead, Sandra J; Trail, Pamela A; Firestone, Raymond A

2002-01-21

The first immunoconjugate of camptothecin has been synthesized wherein the drug is attached to the tumor-recognizing antibody BR96 via a Cathepsin B cleavable linker. Endocytosis of the immunoconjugate upon binding to the tumor cell followed by enzymatic cleavage of the linker inside the endosome ensures tumor-specific release of the drug. In this way, it is hoped that the dose-limiting side effects associated with camptothecin can be eliminated while the antitumor activity is preserved.

Polyphosphoester-Camptothecin Prodrug with Reduction-Response Prepared via Michael Addition Polymerization and Click Reaction.

PubMed

Du, Xueqiong; Sun, Yue; Zhang, Mingzu; He, Jinlin; Ni, Peihong

2017-04-26

Polyphosphoesters (PPEs), as potential candidates for biocompatible and biodegradable polymers, play an important role in material science. Various synthetic methods have been employed in the preparation of PPEs such as polycondensation, polyaddition, ring-opening polymerization, and olefin metathesis polymerization. In this study, a series of linear PPEs has been prepared via one-step Michael addition polymerization. Subsequently, camptothecin (CPT) derivatives containing disulfide bonds and azido groups were linked onto the side chain of the PPE through Cu(I)-catalyzed azidealkyne cyclo-addition "click" chemistry to yield a reduction-responsive polymeric prodrug P(EAEP-PPA)-g-ss-CPT. The chemical structures were characterized by nuclear magnetic resonance spectroscopy, gel permeation chromatography, Fourier transform infrared, ultraviolet-visible spectrophotometer, and high performance liquid chromatograph analyses, respectively. The amphiphilic prodrug could self-assemble into micelles in aqueous solution. The average particle size and morphology of the prodrug micelles were measured by dynamic light scattering and transmission electron microscopy, respectively. The results of size change under different conditions indicate that the micelles possess a favorable stability in physiological conditions and can be degraded in reductive medium. Moreover, the studies of in vitro drug release behavior confirm the reduction-responsive degradation of the prodrug micelles. A methyl thiazolyl tetrazolium assay verifies the good biocompatibility of P(EAEP-PPA) not only for normal cells, but also for tumor cells. The results of cytotoxicity and the intracellular uptake about prodrug micelles further demonstrate that the prodrug micelles can efficiently release CPT into 4T1 or HepG2 cells to inhibit the cell proliferation. All these results show that the polyphosphoester-based prodrug can be used for triggered drug delivery system in cancer treatment.

Thermosensitive mPEG-b-PA-g-PNIPAM comb block copolymer micelles: effect of hydrophilic chain length and camptothecin release behavior.

PubMed

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

2014-02-01

Block copolymer micelles are extensively used as drug controlled release carriers, showing promising application prospects. The comb or brush copolymers are especially of great interest, whose densely-grafted side chains may be important for tuning the physicochemical properties and conformation in selective solvents, even in vitro drug release. The purpose of this work was to synthesize novel block copolymer combs via atom transfer radical polymerization, to evaluate its physicochemical features in solution, to improve drug release behavior and to enhance the bioavailablity, and to decrease cytotoxicity. The physicochemical properties of the copolymer micelles were examined by modulating the composition and the molecular weights of the building blocks. A dialysis method was used to load hydrophobic camptothecin (CPT), and the CPT release and stability were detected by UV-vis spectroscopy and high-performance liquid chromatography, and the cytotoxicity was evaluated by MTT assays. The copolymers could self-assemble into well-defined spherical core-shell micelle aggregates in aqueous solution, and showed thermo-induced micellization behavior, and the critical micelle concentration was 2.96-27.64 mg L(-1). The micelles were narrow-size-distribution, with hydrodynamic diameters about 128-193 nm, depending on the chain length of methoxy polyethylene glycol (mPEG) blocks and poly(N-isopropylacrylamide) (PNIPAM) graft chains or/and compositional ratios of mPEG to PNIPAM. The copolymer micelles could stably and effectively load CPT but avoid toxicity and side-effects, and exhibited thermo-dependent controlled and targeted drug release behavior. The copolymer micelles were safe, stable and effective, and could potentially be employed as CPT controlled release carriers.

Bolus oral glutamine protects rats against CPT-11-induced diarrhea and differentially activates cytoprotective mechanisms in host intestine but not tumor.

PubMed

Xue, Hongyu; Sawyer, Michael B; Field, Catherine J; Dieleman, Levinus A; Murray, David; Baracos, Vickie E

2008-04-01

Dietary glutamine has been suggested to preserve structural and functional integrity of the gut and high dose bolus glutamine has been hypothesized to protect against potentially fatal endotoxic shock, hyperthermic stress, and side effects of chemotherapy. In this study, we aimed to relate the ability of high dose oral bolus glutamine to mitigate the severe diarrhea induced by 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) chemotherapy to specific cytoprotective mechanisms [heat shock response, glutathione (GSH)] in gut and tumor tissues. Female rats bearing Ward colon tumor received CPT-11 (125 mg x kg(-1) x d(-1)x 3 d) with or without an oral glutamine bolus (0.75 g/kg) administered 30 min prior to each CPT-11 dose. Glutamine reduced incidence and severity of late-onset diarrhea following CPT-11 treatment (P < 0.05) and was associated with potentially beneficial and protective responses in the colon: 1) a 3.1- to 7.2-fold increase of heat shock protein (Hsp)25,-70, and -90alpha (P < 0.05); 2) increased reduced GSH (rGSH):oxidized GSH ratio (P < 0.05); 3) prevention of upregulated activity of a key bacterial enzyme (beta-glucuronidase) in the cecal content that mediates CPT-11 intestinal toxicity (P < 0.05); and 4) increased proportions of CD3+CD8+ lymphocytes and memory CD8+ subset in mesenteric lymph nodes following CPT-11 therapy. By contrast, glutamine treatment did not alter CPT-11's antitumor activity, the amino acid concentrations, Hsp expression, or the ratio of rGSH:oxidized GSH in the tumor. Our data demonstrate a striking dichotomy in the response of tumor and host to oral glutamine administration, concurring with the concept that this nutrient may favorably alter the balance between the host and tumor.

An analog of camptothecin inactive against Topoisomerase I is broadly neutralizing of HIV-1 through inhibition of Vif-dependent APOBEC3G degradation.

PubMed

Bennett, Ryan P; Stewart, Ryan A; Hogan, Priscilla A; Ptak, Roger G; Mankowski, Marie K; Hartman, Tracy L; Buckheit, Robert W; Snyder, Beth A; Salter, Jason D; Morales, Guillermo A; Smith, Harold C

2016-12-01

Camptothecin (CPT) is a natural product discovered to be active against various cancers through its ability to inhibit Topoisomerase I (TOP1). CPT analogs also have anti-HIV-1 (HIV) activity that was previously shown to be independent of TOP1 inhibition. We show that a cancer inactive CPT analog (O2-16) inhibits HIV infection by disrupting multimerization of the HIV protein Vif. Antiviral activity depended on the expression of the cellular viral restriction factor APOBEC3G (A3G) that, in the absence of functional Vif, has the ability to hypermutate HIV proviral DNA during reverse transcription. Our studies demonstrate that O2-16 has low cytotoxicity and inhibits Vif-dependent A3G degradation, enabling A3G packaging into HIV viral particles that results in A3G signature hypermutations in viral genomes. This antiviral activity was A3G-dependent and broadly neutralizing against sixteen HIV clinical isolates from groups M (subtypes A-G), N, and O as well as seven single and multi-drug resistant strains of HIV. Molecular modeling predicted binding near the PPLP motif crucial for Vif multimerization and activity. O2-16 also was active in blocking Vif degradation of APOBEC3F (A3F). We propose that CPT analogs not active against TOP1 have novel therapeutic potential as Vif antagonists that enable A3G-dependent hypermutation of HIV. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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

Medicinally important secondary metabolites in recombinant microorganisms or plants: progress in alkaloid biosynthesis.

PubMed

Schäfer, Holger; Wink, Michael

2009-12-01

Plants produce a high diversity of natural products or secondary metabolites which are important for the communication of plants with other organisms. A prominent function is the protection against herbivores and/or microbial pathogens. Some natural products are also involved in defence against abiotic stress, e.g. UV-B exposure. Many of the secondary metabolites have interesting biological properties and quite a number are of medicinal importance. Because the production of the valuable natural products, such as the anticancer drugs paclitaxel, vinblastine or camptothecin in plants is a costly process, biotechnological alternatives to produce these alkaloids more economically become increasingly important. This review provides an overview of the state of art to produce alkaloids in recombinant microorganisms, such as bacteria or yeast. Some progress has been made in metabolic engineering usually employing a single recombinant alkaloid gene. More importantly, for benzylisoquinoline, monoterpene indole and diterpene alkaloids (taxanes) as well as some terpenoids and phenolics the proof of concept for production of complex alkaloids in recombinant Escherichia coli and yeast has already been achieved. In a long-term perspective, it will probably be possible to generate gene cassettes for complete pathways, which could then be used for production of valuable natural products in bioreactors or for metabolic engineering of crop plants. This will improve their resistance against herbivores and/or microbial pathogens.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akao, Yukihiro; Banno, Yoshiko; Nakagawa, Yoshihito

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}more » 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.« less

Relationship between DNA damage response, initiated by camptothecin or oxidative stress, and DNA replication, analyzed by quantitative 3D image analysis.

PubMed

Berniak, K; Rybak, P; Bernas, T; Zarębski, M; Biela, E; Zhao, H; Darzynkiewicz, Z; Dobrucki, J W

2013-10-01

A method of quantitative analysis of spatial (3D) relationship between discrete nuclear events detected by confocal microscopy is described and applied in analysis of a dependence between sites of DNA damage signaling (γH2AX foci) and DNA replication (EdU incorporation) in cells subjected to treatments with camptothecin (Cpt) or hydrogen peroxide (H2O2). Cpt induces γH2AX foci, likely reporting formation of DNA double-strand breaks (DSBs), almost exclusively at sites of DNA replication. This finding is consistent with the known mechanism of induction of DSBs by DNA topoisomerase I (topo1) inhibitors at the sites of collisions of the moving replication forks with topo1-DNA "cleavable complexes" stabilized by Cpt. Whereas an increased level of H2AX histone phosphorylation is seen in S-phase of cells subjected to H2O2, only a minor proportion of γH2AX foci coincide with DNA replication sites. Thus, the increased level of H2AX phosphorylation induced by H2O2 is not a direct consequence of formation of DNA lesions at the sites of moving DNA replication forks. These data suggest that oxidative stress induced by H2O2 and formation of the primary H2O2-induced lesions (8-oxo-7,8-dihydroguanosine) inhibits replication globally and triggers formation of γH2AX at various distances from replication forks. Quantitative analysis of a frequency of DNA replication sites and γH2AX foci suggests also that stalling of replicating forks by Cpt leads to activation of new DNA replication origins. © 2013 International Society for Advancement of Cytometry. Copyright © 2013 International Society for Advancement of Cytometry.

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. Copyright © 2013 Elsevier B.V. All rights reserved.

Novel tumor-targeted RGD peptide-camptothecin conjugates: synthesis and biological evaluation.

PubMed

Dal Pozzo, Alma; Ni, Ming-Hong; Esposito, Emiliano; Dallavalle, Sabrina; Musso, Loana; Bargiotti, Alberto; Pisano, Claudio; Vesci, Loredana; Bucci, Federica; Castorina, Massimo; Foderà, Rosanna; Giannini, Giuseppe; Aulicino, Concetta; Penco, Sergio

2010-01-01

Five RGD peptide-camptothecin (CPT) conjugates were designed and synthesized with the purpose to improve the therapeutic index of this antitumoral drug family. New RGD cyclopeptides were selected on the basis of their high affinity to alpha(v) integrin receptors overexpressed by tumor cells and their metabolic stability. The conjugates can be divided in two groups: in the first the peptide was attached to the drug through an amide bond, in the second through a hydrazone bond. The main difference between the two spacers lies in their acid stability. Affinity to the receptors was maintained for all conjugates and their internalization into tumor cells was demonstrated. The first group conjugates showed lower in vitro and in vivo activity than the parent drug, probably due to the excessive stability of the amide bond, even inside the tumor cells. Conversely, the hydrazone conjugates exhibited in vitro tumor cell inhibition similar to the parent drug, indicating high conversion in the culture medium and/or inside the cells, but their poor solubility hampered in vivo experiments. On the basis of these results, information was acquired for additional development of derivatives with different linkers and better solubility for in vivo evaluation. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

The N+CPT resonance

NASA Astrophysics Data System (ADS)

Crescimanno, Michael; Hohensee, Michael; Hancox, Cindy; Phillips, David; Walsworth, Ron

2007-06-01

Of relevance to compact atomic frequency standards, we investigate a model of the N+CPT joint optical resonance. We compare analytical solutions of a 4-state theory, as well as numerical solutions of the optical Bloch equations, to experimental investigations of N+CPT resonances in 87Rb. Our results inform the optimization of N+CPT based frequency standards.

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging.

PubMed

Tabanor, Kayann; Lee, Phil; Kiptoo, Paul; Choi, In-Young; Sherry, Erica B; Eagle, Cheyenne Sun; Williams, Todd D; Siahaan, Teruna J

2016-02-01

Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new noninvasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (iv) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain.

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging

PubMed Central

Tabanor, Kayann; Lee, Phil; Kiptoo, Paul; Choi, In-Young; Sherry, Erica B.; Eagle, Cheyenne Sun; Williams, Todd D.; Siahaan, Teruna J.

2015-01-01

Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new non-invasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (i.v.) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain. PMID:26705088

Total Synthesis and Biological Evaluation of 22-Hydroxyacuminatine

PubMed Central

Xiao, Xiangshu; Antony, Smitha; Pommier, Yves; Cushman, Mark

2008-01-01

A total synthesis of 22-hydroxyacuminatine, a cytotoxic alkaloid isolated from Camptotheca acuminata, is reported. The key step in the synthesis involves the reaction of 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline with a brominated phthalide to generate a substituted pentacyclic 12H-5,11a-diazadibenzo[b,h]fluoren-11-one intermediate. Despite its structural resemblance to camptothecin and luotonin A, a biological evaluation of 22-hydroxyacuminatine in a topoisomerase I-deficient cell line P388/CPT45 has confirmed that the observed cytotoxicity is not due to topoisomerase I inhibition. This result is consistent with the hypothesis that π-π stacking is more important than hydrogen bonding interactions in determining topoisomerase I inhibitor binding in the ternary cleavage complex. PMID:16480276

Anti-Fas Antibody Conjugated Nanoparticles Enhancing the Antitumor Effect of Camptothecin by Activating the Fas-FasL Apoptotic Pathway.

PubMed

Yu, Hongliang; He, Jian; Lu, Qian; Huo, Da; Yuan, Shanmei; Zhou, Zhengyang; Xu, Peipei; Hu, Yong

2016-11-09

Emerging evidence suggest that the introduction of Fas ligand (FasL) can enhance the Fas-dependent apoptosis and induce durable immune responses against tumor. However, selective triggering of apoptosis in tumor cells while sparing normal cells remains a great challenge for the application of FasL-based therapeutic strategies. Herein, smart nanoparticles (NPs) with a sandwich structure were fabricated. These NPs consist of a matrix metalloproteinase (MMP) cleavable PEG outer layer, an anti-Fas antibody middle layer, and a camptothecin (CPT)-loaded inner core. They could accumulate at a tumor site by the enhanced permeability and retention (EPR) effect. The removable PEG layer protects the cytotoxic anti-Fas antibody from premature contact with normal tissues, thus avoiding the unexpected lethal side effect before they reach the tumor site. Due to the high level of MMP expressed by tumor cells inside the tumor tissue, these NPs would shed their PEG layers, resulting in the exposure of anti-Fas antibody to bind the Fas receptor and triggering the apoptosis of tumor cells. Results of Western blot confirmed that these NPs could mimic the function of activated cytotoxic lymphocyte (CTL) to activate the Fas-FasL apoptosis pathway of tumor cells. With the aid of CPT payload, these anti-Fas antibody conjugated NPs achieved a high tumor inhibition in the B16 allograft tumor animal model. The design of these NPs provides a method for delivering cytotoxic ligand to targeting tissue, which may be valuable in cancer therapy.

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

Camptotheca acuminata 10-hydroxycamptothecin O-methyltransferase: an alkaloid biosynthetic enzyme coopted from flavonoid metabolism.

PubMed

Salim, Vonny; Jones, A Daniel; DellaPenna, Dean

2018-04-22

The medicinal plant Camptotheca acuminata accumulates camptothecin, 10-hydroxycamptothecin, and 10-methoxycamptothecin as its major bioactive monoterpene indole alkaloids. Here, we describe identification and functional characterization of 10-hydroxycamptothecin O-methyltransferase (Ca10OMT), a member of the Diverse subclade of Class II OMTs. Ca10OMT is highly active toward both its alkaloid substrate and a wide range of flavonoids in vitro and in this way contrasts with other alkaloid OMTs in the subclade that only utilize alkaloid substrates. Ca10OMT shows a strong preference for the A-ring 7-OH of flavonoids, which is structurally equivalent to the 10-OH of 10-hydroxycamptothecin. The substrates of other alkaloid OMTs in the subclade bear little similarity to flavonoids, but the 3-D positioning of the 7-OH, A- and C-rings of flavonoids is nearly identical to the 10-OH, A- and B-rings of 10-hydroxycamptothecin. This structural similarity likely explains the retention of flavonoid OMT activity by Ca10OMT and also why kaempferol and quercetin aglycones are potent inhibitors of its 10-hydroxycamptothecin activity. The catalytic promiscuity and strong inhibition of Ca10OMT by flavonoid aglycones in vitro prompted us to investigate the potential physiological roles of the enzyme in vivo. Based on its regioselectivity, kinetic parameters and absence of 7-OMT flavonoids in vivo, we conclude that the major and likely only substrate of Ca10OMT in vivo is 10-hydroxycamptothecin. This is likely accomplished by Ca10OMT being kept spatially separated at the tissue levels from potentially inhibitory flavonoid aglycones, and flavonoid aglycones being rapidly glycosylated to non-inhibitory flavonoid glycosides. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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.

Smart AS1411-aptamer conjugated pegylated PAMAM dendrimer for the superior delivery of camptothecin to colon adenocarcinoma in vitro and in vivo.

PubMed

Alibolandi, Mona; Taghdisi, Seyed Mohammad; Ramezani, Pouria; Hosseini Shamili, Fazileh; Farzad, Sara Amel; Abnous, Khalil; Ramezani, Mohammad

2017-03-15

In the current study camptothecin-loaded pegylated PAMAM dendrimer were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against colorectal cancer cells which over expresses nucleolin receptors. The morphological properties and size dispersity of the prepared nanoparticles were evaluated using transmission electron microscope (TEM) and DLS. The drug-loading content and encapsulation efficiency were obtained 8.1% and 93.67% respectively. The in vitro release of camptothecin from the formulation was provided the sustained release of encapsulated camptothecin during 4days. Comparative in vitro cytotoxicity experiments demonstrated that the targeted camptothecin loaded-pegylated dendrimers had higher antiproliferation activity, towards nucleolin-positive HT29 and C26 colorectal cancer cells than nucleolin-negative CHO cell line. Fluorscence microscopy and flow cytometry also confirmed the enhanced cellular uptake of AS1411 targeted pegylated-dendrimer. In vivo study in C26 tumor-bearing BALB/C mice revealed that the AS1411-functionalized camptothecin loaded pegylated dendrimers improved antitumor activity and survival rate of the encapsulated camptothecin. Conjugation of AS1411 aptamer to the camptothecin loaded-pegylated dendrimer surface provides site-specific delivery of camptothecin, inhibit C26 tumor growth in vivo and significantly decrease systemic toxicity. These results suggested that the new nucleolin-targeted pegylated PAMAM dendrimer as a delivery system for camptothecin have the potential for the treatment of nucleolin-overexpressed colorectal cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Interspecies scaling of a camptothecin analogue: human predictions for intravenous topotecan using animal data.

PubMed

Ahlawat, P; Srinivas, N R

2008-11-01

As a class, camptothecin analogues via market entry of topotecan and irinotecan, have shown promise for the treatment of various solid tumours. Topotecan, in particular, was chosen as the substrate for allometric scaling and prediction of human parameter values for both total clearance (CL) and volume of distribution (V(ss)). The availability of published data in mouse, rat, dog, and monkey paved the way for interspecies scaling via allometry. Although it appeared that at a minimum mouse, rat, and dog would reasonably fit in a three-species allometry scale-up, the inclusion of monkey data enabled a better prediction of the human parameter values for total topotecan-e.g., CL: allometric equation: 1.5234W(0.7865); predicted value = 43.04 l h(-1): observed CL = 24-53 l h(-1); V(ss): allometric equation: 1.1939W(1.0208); predicted value = 91.29 litres: observed V(ss) = 66-146 litres. The proximity of the allometric exponent values of CL (0.7885) and V(ss) (1.0208) to the suggested values of 0.75 and 1.00 was not only encouraging, but also confirmed the applicability of interspecies scaling approach for topotecan. The data suggest that allometric scaling approaches with suitable correction factors could potentially be used to predict the human pharmacokinetics of novel CPT analogues prospectively.

Neutrinos as the messengers of CPT violation

NASA Astrophysics Data System (ADS)

Borissov, Liubomir Anguelov

CPT violation has the potential to explain all three existing neutrino oscillation signals without enlarging the neutrino sector. CPT violation in the Dirac mass terms of the three neutrino flavors preserves Lorentz invariance, but generates in dependent masses for neutrinos and antineutrinos. This specific signature can be motivated by braneworld scenarios with extra dimensions, where neutrinos are the natural messengers for Standard Model physics of CPT violation in the bulk. A simple model of maximal CPT violation is sufficient to explain the exisiting neutrino data, while accommodating the recent results from the KamLAND experiment and making dramatic predictions for the ongoing MiniBooNE experiment. In addition, the model fits the existing SuperKamiokande data, at least as well as the standard atmospheric neutrino oscillation models. Another attractive feature of the presented model is that it provides a new promising mechanism for baryogenesis, which obviates two of the three Sakharov conditions necessary to generate the baryon asymmetry of the universe. CPT-violating scenarios can give new insights about the possible nature of neutrinos. Majorana neutrino masses are still allowed, but in general, there are no longer Majorana neutrinos in the conventional sense. However, CPT-violating models still have interesting consequences for neutrinoless double beta decay. Compared to the usual case, while the larger mass scale (from LSND) may appear, a greater degree of suppression can also occur.

Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture of colon tumour cell spheroids with normal cells after incubation with rhTGF- beta1 and/or CPT-11.

PubMed

Paduch, Roman; Jakubowicz-Gil, Joanna; Kandefer-Szerszen, Martyna

2009-12-01

We studied the expression of inducible heat shock protein (HSP27, HSP72) and multidrug-resistance protein (MRP) in co-cultures of human colon carcinoma cell spheroids obtained from different grades of tumour with normal human colon epithelium, myofibroblast and endothelial cell monolayers. We also measured the influence of recombinant human transforming growth factor beta1 (rhTGF-beta1) and camptothecin (CPT-11), added as single agents or in combination, on the levels of the HSPs, MRP, interleukin (IL)-6 and nitric oxide (NO). An immunoblotting analysis with densitometry showed that rhTGF-beta1 and/or CPT-11 increased HSP27, HSP72 and MRP expression in tumour cells and myofibroblasts, as well as in co-cultures compared with appropriate controls. By contrast, in colonic epithelium, inhibition of HSPs and MRP was comparable with that of the control. In endothelial cells, HSP72 was undetectable. Direct interaction of colon tumour spheroids with normal myofibroblasts caused a significant, tumour-grade dependent increase in IL-6 production. Production of IL-6 was significantly lowered by rhTGF-beta1 and/or CPT-11. Tumour cell spheroids cultivated alone produced larger amounts of NO than normal cells. In co-culture, the level of the radical decreased compared with the sum of NO produced by the monocultures of the two types of cells. rhTGF-beta1 and/or CPT-11 decreased NO production both in tumour and normal cell monocultures and their co-cultures. In conclusion, direct interactions between tumour and normal cells influence the expression of HSP27, HSP72 and MRP, and alter IL-6 and NO production. rhTGF-beta1 and/or CPT-11 may potentate resistance to chemotherapy by increasing HSP and MRP expression but, on the other hand, they may limit tumour cell spread by decreasing the level of some soluble mediators of inflammation (IL-6 and NO).

A polarization converting device for an interfering enhanced CPT atomic clock.

PubMed

Wang, Kewei; Tian, Yuan; Yin, Yi; Wang, Yuanchao; Gu, Sihong

2017-11-01

With interfering enhanced coherent population trapping (CPT) signals, a CPT atomic clock with improved frequency stability performance can be realized. We explore an optical device that converts single-polarized bichromatic light to left and right circularly polarized superposed bichromatic light to generate interfering enhanced CPT resonance with atoms. We have experimentally studied a tabletop CPT atomic clock apparatus with a microfabricated 87 Rb atomic chip-scale cell, and the study results show that it is promising to realize a compact CPT atomic clock, even a chip-scale CPT atomic clock through microfabrication, with improved frequency stability performance.

A polarization converting device for an interfering enhanced CPT atomic clock

NASA Astrophysics Data System (ADS)

Wang, Kewei; Tian, Yuan; Yin, Yi; Wang, Yuanchao; Gu, Sihong

2017-11-01

With interfering enhanced coherent population trapping (CPT) signals, a CPT atomic clock with improved frequency stability performance can be realized. We explore an optical device that converts single-polarized bichromatic light to left and right circularly polarized superposed bichromatic light to generate interfering enhanced CPT resonance with atoms. We have experimentally studied a tabletop CPT atomic clock apparatus with a microfabricated 87Rb atomic chip-scale cell, and the study results show that it is promising to realize a compact CPT atomic clock, even a chip-scale CPT atomic clock through microfabrication, with improved frequency stability performance.

Cystic pancreatic tumors (CPT): predictors of malignant behavior.

PubMed

Javle, Milind; Shah, Pankaj; Yu, Jihnhee; Bhagat, Vishal; Litwin, Alan; Iyer, Renuka; Gibbs, John

2007-03-01

Due to widespread use of imaging studies, increasing cystic pancreatic tumor (CPT) cases are being detected. The diagnosis of malignancy in CPT cases requires pancreatectomy. Clinical and laboratory characteristics of CPT may predict underlying malignancy. CPT cases treated between 1994 and 2004 at our institution were included. Pseudocysts were excluded. Serous cystadenoma (SCA), mucinous cystadenoma (MCA), intrapapillary mucinous tumor, cystic endocrine tumor, and lymphoepithelial cysts were classified as benign or pre-malignant. Serous cystadenocarcinoma (SCACA), mucinous cystadenocarcinoma (MCACA), and adenocarcinoma (ACA) were classified as malignant. Thirty-five patients had histological confirmation. Median age was 65 years. Male/female ratio was higher in malignant group (P = 0.0284). Weight loss and abdominal mass were more prevalent in malignant group (P = 0.042 and 0.028, respectively). Malignant lesions were larger, associated with local invasion (superior mesenteric artery (SMA), superior mesenteric vein (SMV), portal vein (PV) complex or celiac encasement) and CA 19-9 elevation. On univariate analyses, local invasion (P = 0.0029), negative surgical intervention (P = 0.0010), presence of ACA (P = 0.0044), or malignant CPT (P = 0.0018) were associated with shorter survival. On a multivariate analysis, local invasion was associated with shorter survival [Hazard ratio (HR) = 4.322, P = 0.0218], while surgical intervention was associated with improved survival (HR = 0.179, P = 0.0124). Male sex, abdominal mass, weight loss, larger tumor size, local invasion, and elevated CA 19-9 were associated with malignant CPT.

Neutrinos, DUNE and the world best bound on CPT invariance

NASA Astrophysics Data System (ADS)

Barenboim, G.; Ternes, C. A.; Tórtola, M.

2018-05-01

CPT symmetry, the combination of Charge Conjugation, Parity and Time reversal, is a cornerstone of our model building strategy and therefore the repercussions of its potential violation will severely threaten the most extended tool we currently use to describe physics, i.e. local relativistic quantum fields. However, limits on its conservation from the Kaon system look indeed imposing. In this work we will show that neutrino oscillation experiments can improve this limit by several orders of magnitude and therefore are an ideal tool to explore the foundations of our approach to Nature. Strictly speaking testing CPT violation would require an explicit model for how CPT is broken and its effects on physics. Instead, what is presented in this paper is a test of one of the predictions of CPT conservation, i.e., the same mass and mixing parameters in neutrinos and antineutrinos. In order to do that we calculate the current CPT bound on all the neutrino mixing parameters and study the sensitivity of the DUNE experiment to such an observable. After deriving the most updated bound on CPT from neutrino oscillation data, we show that, if the recent T2K results turn out to be the true values of neutrino and antineutrino oscillations, DUNE would measure the fallout of CPT conservation at more than 3σ. Then, we study the sensitivity of the experiment to measure CPT invariance in general, finding that DUNE will be able to improve the current bounds on Δ (Δ m312) by at least one order of magnitude. We also study the sensitivity to the other oscillation parameters. Finally we show that, if CPT is violated in nature, combining neutrino with antineutrino data in oscillation analysis will produce imposter solutions.

A conjugate of camptothecin and a somatostatin analog against prostate cancer cell invasion via a possible signaling pathway involving PI3K/Akt, alphaVbeta3/alphaVbeta5 and MMP-2/-9.

PubMed

Sun, Li-Chun; Luo, Jing; Mackey, L Vienna; Fuselier, Joseph A; Coy, David H

2007-02-08

Camptothecin (CPT) was conjugated to the N-terminal of a somatostatin analog (SSA) directly via a carbamate group and a basic N-terminal linking motif, D-Lys-D-Tyr-Lys-D-Tyr-D-Lys. This new CPT-SSA conjugate termed JF-10-81 was evaluated as a receptor-specific delivery system for its anti-invasive and anti-angiogenic activities. It was found that, in addition to blocking migration and invasion of highly invasive prostate cancer PC-3 cells, this conjugate also inhibited in vitro capillary-like tube formation of endothelial cells and in vivo angiogenesis in C57B1/6N female mice. JF-10-81 was found to block PC-3 cell attachment to various extracellular matrix components, mainly to vitronectin, the ligand of cell surface receptors integrin alphaVbeta3 and alphaVbeta5. Additionally, JF-10-81 reduced expression of integrins alphaVbeta3 and alphaVbeta5 on PC-3 cell surfaces, without effects on beta1 or any alphabeta1 heterodimers. This conjugate also inactivated phosphorylation of protein kinase B (PKB/Akt), down-regulated the expression of latent matrix metalloproteinase (MMP) -2 and MMP-9, but had little effect on MMP-3/-10. Meanwhile, membrane type-1 matrix metalloproteinase (MT1-MMP) and the tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) were not detectable in PC-3 cells. alphaVbeta3/alphaVbeta5 and MMP-2/-9 are known to be highly expressed in many tumor cells and play an important role in tumor progression. Our results support that this conjugate could possibly inhibit prostate cancer PC-3 cell invasion through a signaling pathway involving PI3K/Akt, alphaVbeta3/alphaVbeta5 and MMP-2/-9, and this SSA could be used as an efficient vector to deliver CPT or other cytotoxic agents to target sites for cancer therapy.

Selective Cytotoxicity and Combined Effects of Camptothecin or Paclitaxel with Sodium-R-Alpha Lipoate on A549 Human Non-Small Cell Lung Cancer Cells

PubMed Central

Ibrahim, Sherif; Gao, Dayuan; Sinko, Patrick J.

2013-01-01

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the deadliest form of cancer in the US and worldwide. New therapies are highly sought after to improve outcome. The effect of sodium-R-alpha lipoate on camptothecin- and paclitaxel-induced cytotoxicity was evaluated on A549 NSCLC and BEAS-2B ‘normal’ lung epithelial cells. Combination indices (CI) and dose reduction indices (DRI) were investigated by studying the cytotoxicity of sodium-R-alpha lipoate (0–16 mM), camptothecin (0–25 nM) and paclitaxel (0–0.06 nM) alone and in combination. 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium-bromide (MTT) was used to assess cytotoxicity. The combinational cytotoxic effects of sodium-R-alpha lipoate with camptothecin or paclitaxel were analyzed using a simulation of dose effects (CompuSyn®3.01). The effects of sodium-R-alpha lipoate on camptothecin- and paclitaxel-induced cytotoxicity varied based on concentrations and treatment times. It was found that sodium-R-alpha lipoate wasn’t cytotoxic towards BEAS-2B cells at any of the concentrations tested. For A549 cells, CIs [(additive (CI=1); synergistic (CI<1); antagonistic (CI>1)] were lower and DRIs were higher for the camptothecin/sodium-R-alpha-lipoate combination (CI=~0.17–1.5; DRI=~2.2–22.6) than the paclitaxel/sodium-R-alpha-lipoate combination (CI=~0.8–9.9; DRI=~0.10–5.8) suggesting that the camptothecin regimen was synergistic and that the addition of sodium-R-alpha lipoate was important for reducing the camptothecin dose and potential for adverse effects. PMID:24063429

Alkaloids in Marine Algae

PubMed Central

Güven, Kasım Cemal; Percot, Aline; Sezik, Ekrem

2010-01-01

This paper presents the alkaloids found in green, brown and red marine algae. Algal chemistry has interested many researchers in order to develop new drugs, as algae include compounds with functional groups which are characteristic from this particular source. Among these compounds, alkaloids present special interest because of their pharmacological activities. Alkaloid chemistry has been widely studied in terrestrial plants, but the number of studies in algae is insignificant. In this review, a detailed account of macro algae alkaloids with their structure and pharmacological activities is presented. The alkaloids found in marine algae may be divided into three groups: 1. Phenylethylamine alkaloids, 2. Indole and halogenated indole alkaloids, 3. Other alkaloids. PMID:20390105

The CPT Reading Comprehension Test: A Validity Study.

ERIC Educational Resources Information Center

Napoli, Anthony R.; Raymond, Lanette A.; Coffey, Cheryl A.; Bosco, Diane M.

1998-01-01

Describes a study done at Suffolk County Community College (New York) that assessed the validity of the College Board's Computerized Placement Test in Reading Comprehension (CPT-R) by comparing test results of 1,154 freshmen with the results of the Degree of Power Reading Test. Results confirmed the CPT-R's reliability in identifying basic…

Metabolomic profiling reveals a role for CPT1c in neuronal oxidative metabolism.

PubMed

Lee, Jieun; Wolfgang, Michael J

2012-10-25

Carnitine Palmitoyltransferase-1c (CPT1c) is a neuron specific homologue of the carnitine acyltransferase family of enzymes. CPT1 isoenzymes transfer long chain acyl groups to carnitine. This constitutes a rate setting step for mitochondrial fatty acid beta-oxidation by facilitating the initial step in acyl transfer to the mitochondrial matrix. In general, neurons do not heavily utilize fatty acids for bioenergetic needs and definitive enzymatic activity has been unable to be demonstrated for CPT1c. Although there are studies suggesting an enzymatic role of CPT1c, its role in neurochemistry remains elusive. In order to better understand how CPT1c functions in neural metabolism, we performed unbiased metabolomic profiling on wild-type (WT) and CPT1c knockout (KO) mouse brains. Consistent with the notion that CPT1c is not involved in fatty acid beta-oxidation, there were no changes in metabolites associated with fatty acid oxidation. Endocannabinoids were suppressed in the CPT1c KO, which may explain the suppression of food intake seen in CPT1c KO mice. Although products of beta-oxidation were unchanged, small changes in carnitine and carnitine metabolites were observed. Finally, we observed changes in redox homeostasis including a greater than 2-fold increase in oxidized glutathione. This indicates that CPT1c may play a role in neural oxidative metabolism. Steady-state metabolomic analysis of CPT1c WT and KO mouse brains identified a small number of metabolites that differed between CPT1c WT and KO mice. The subtle changes in a broad range of metabolites in vivo indicate that CPT1c does not play a significant or required role in fatty acid oxidation; however, it could play an alternative role in neuronal oxidative metabolism.

Sonic CPT Probing in Support of DNAPL Characterization

DTIC Science & Technology

2000-11-21

directed at developing advanced sensors for delivery by the cone penetrometer. To accommodate these new sensors , probe sizes have increased (from 1.44-in...capability of the CPT, a sonic vibratory system was integrated with conventional CPT to advance cone penetrometer sensor packages past currently attainable...Sonic, Cone Penetrometer, Site Characterization, Fluorescense, Sensor , Shock Hardened Sensors , Geoprobe• 17. SECURITY CLASSIFICATION OF REPORT

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.

Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Zhong-Ze; Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian

Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showedmore » that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4{sup +} naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression. - Highlights: • CPT-11 is an effective anticancer drug, but induced toxicity limits its application in the clinic. • CPT-11 decreased IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes. • CPT-11 altered the composition of bile acid metabolites, notably DCA and TDCA in liver, bile and intestine. • DCA and TDCA potentiated CPT-11-induced suppression of IL-10 secretion by active CD4{sup +} naive T cells.« less

CPT-11 activates NLRP3 inflammasome through JNK and NF-κB signalings

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Qian; Zhang, Xiong; Wang, Weicheng

CPT-11 is widely used for cancer therapy as a chemotherapeutic agent. Despite its good efficacy, a large number of side effects appeared during decades of clinical application. Delayed diarrhea, at dose limiting toxicity, happens after 24 h of treatment and the rate of occurrence is up to 90%. Although many investments have been made on this negative impact, the real molecular mechanism of delayed diarrhea is poorly understood. In this study, we have discovered that CPT-11 promotes macrophage infiltration into intestinal tissues and activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, resulting in a robust IL-1β responsemore » and colonic inflammation similar to DSS (dextran sodium sulfate) induced experimental colitis. CPT-11 plus LPS primed mouse bone marrow-derived macrophages (BMDMs) and human acute monocytic leukemia cells (THP-1 cells) staying in a highly activated status, showing increased caspase-1 activity and releasing great amounts of IL-1β and IL-18 as detected by ELISA and western blot. A further mechanism showed that JNK and NF-κB signaling pathways participated in inflammatory responses activated by CPT-11. These results prompted us to suggest that the NLRP3-IL-1β signaling pathway might play an important role in CPT11-induced colitis. Our findings provide a basis for developing novel strategies that improve clinical implications of CPT-11. - Highlights: • CPT-11 induced experimental colitis in vivo. • CPT-11 induced intestine injury and macrophage infiltration. • CPT-11 significantly elevated levels of macrophage derived inflammatory cytokines in mice intestines. • CPT-11 activated NLRP3 inflammasome in vitro and in vivo. • CPT-11 activated JNK and NF-κB signalings in THP-1 and BMDMs.« less

Two- and four-dimensional representations of the PT - and CPT -symmetric fermionic algebras

NASA Astrophysics Data System (ADS)

Beygi, Alireza; Klevansky, S. P.; Bender, Carl M.

2018-03-01

Fermionic systems differ from their bosonic counterparts, the main difference with regard to symmetry considerations being that T2=-1 for fermionic systems. In PT -symmetric quantum mechanics an operator has both PT and CPT adjoints. Fermionic operators η , which are quadratically nilpotent (η2=0 ), and algebras with PT and CPT adjoints can be constructed. These algebras obey different anticommutation relations: η ηPT+ηPTη =-1 , where ηPT is the PT adjoint of η , and η ηCPT+ηCPTη =1 , where ηCPT is the CPT adjoint of η . This paper presents matrix representations for the operator η and its PT and CPT adjoints in two and four dimensions. A PT -symmetric second-quantized Hamiltonian modeled on quantum electrodynamics that describes a system of interacting fermions and bosons is constructed within this framework and is solved exactly.

Kampo medicine "Dai-kenchu-to" prevents CPT-11-induced small-intestinal injury in rats.

PubMed

Chikakiyo, Motoya; Shimada, Mitsuo; Nakao, Toshihiro; Higashijima, Jun; Yoshikawa, Kozo; Nishioka, Masanori; Iwata, Takashi; Kurita, Nobuhiro

2012-01-01

The key anticancer agent, CPT-11 (irinotecan hydrochloride), induces severe diarrhea clinically. We investigated the effect of a Kampo medicine, Dai-kenchu-to (DKT), on CPT-11-induced intestinal injuries in rats. Twenty-four male Wistar rats were divided into three groups: a control group; a CPT-11 group, given CPT-11 150 mg/kg intraperitoneally for 2 days; and a DKT group, given DKT 300 mg/kg orally for 5 days with CPT-11 150 mg/kg intraperitoneally on days 4 and 5. The rats were killed on day 6. Interleukin (IL)-1β, IL-12, interferon (IFN)-γ, and tumor necrosis factor-α expression in the small intestine of the CPT-11 group was significantly higher than that of the control group. Interleukin-1β and IFN-γ expression was improved significantly by DKT (P < 0.05). The number and height of jejuna villi, injury score, and apoptosis index in the CPT-11 group were improved significantly by DKT (P < 0.05). DKT suppressed CPT-11 induced inflammatory cytokines and apoptosis in the intestinal mucosa and maintained the mucosal integrity.

Dendrobium nobile Lindl. alkaloids regulate metabolism gene expression in livers of mice.

PubMed

Xu, Yun-Yan; Xu, Ya-Sha; Wang, Yuan; Wu, Qin; Lu, Yuan-Fu; Liu, Jie; Shi, Jing-Shan

2017-10-01

In our previous studies, Dendrobium nobile Lindl. alkaloids (DNLA) has been shown to have glucose-lowering and antihyperlipidaemia effects in diabetic rats, in rats fed with high-fat diets, and in mice challenged with adrenaline. This study aimed to examine the effects of DNLA on the expression of glucose and lipid metabolism genes in livers of mice. Mice were given DNLA at doses of 10-80 mg/kg, po for 8 days, and livers were removed for total RNA and protein isolation to perform real-time RT-PCR and Western blot analysis. Dendrobium nobile Lindl. alkaloids increased PGC1α at mRNA and protein levels and increased glucose metabolism gene Glut2 and FoxO1 expression. DNLA also increased the expression of fatty acid β-oxidation genes Acox1 and Cpt1a. The lipid synthesis regulator Srebp1 (sterol regulatory element-binding protein-1) was decreased, while the lipolysis gene ATGL was increased. Interestingly, DNLA increased the expression of antioxidant gene metallothionein-1 and NADPH quinone oxidoreductase-1 (Nqo1) in livers of mice. Western blot on selected proteins confirmed these changes including the increased expression of GLUT4 and PPARα. DNLA has beneficial effects on liver glucose and lipid metabolism gene expressions, and enhances the Nrf2-antioxidant pathway gene expressions, which could play integrated roles in regulating metabolic disorders. © 2017 Royal Pharmaceutical Society.

[Alkaloids of Pausinystalia macroceras].

PubMed

Leboef, M; Cavé, A; Mangeney, P; Bouquet, A

1981-04-01

A study of the alkaloidal content of trunk-barks of Pausinystalia macroceras (K. Schum.) Pierre, Rubiaceae, resulted in the isolation of six alkaloids, five of which are indole alkaloids that belong to the yohimbane and heteroyohimbane groups; among them, yohimbine was found in major amount. Moreover, the levorotatory isomer of calycanthine, a quinoline dimeric tryptophane derived base, has been isolated for the first time. The phytochemical significance of calycanthine and related alkaloids is discussed.

CPT-11-Induced Delayed Diarrhea Develops via Reduced Aquaporin-3 Expression in the Colon

PubMed Central

Kon, Risako; Tsubota, Yuika; Minami, Moe; Kato, Saki; Matsunaga, Yukari; Kimura, Hiroshi; Murakami, Yuta; Fujikawa, Tetsuya; Sakurai, Ryoya; Tomimoto, Rei; Machida, Yoshiaki; Ikarashi, Nobutomo; Sugiyama, Kiyoshi

2018-01-01

While irinotecan (CPT-11) has a potent anti-cancer effect, it also causes serious diarrhea as an adverse reaction. In this study, we analyzed the pathogenic mechanism of CPT-11-induced delayed diarrhea by focusing on water channel aquaporin-3 (AQP3) in the colon. When rats received CPT-11, the expression level of AQP3 was reduced during severe diarrhea. It was found that the expression levels of inflammatory cytokines and the loss of crypt cells were increased in the colon when CPT-11 was administered. When celecoxib, an anti-inflammatory drug, was concomitantly administered, both the diarrhea and the reduced expression of AQP3 induced by CPT-11 were suppressed. The inflammation in the rat colon during diarrhea was caused via activated macrophage by CPT-11. These results showed that when CPT-11 is administered, the expression level of AQP3 in the colon is reduced, resulting in delayed diarrhea by preventing water transport from the intestinal tract. It was also suggested that the reduced expression of AQP3 might be due to the inflammation that occurs following the loss of colonic crypt cells and to the damage caused by the direct activation of macrophages by CPT-11. Therefore, it was considered that anti-inflammatory drugs that suppress the reduction of AQP3 expression could prevent CPT-11-induced delayed diarrhea. PMID:29316651

CPT-11-Induced Delayed Diarrhea Develops via Reduced Aquaporin-3 Expression in the Colon.

PubMed

Kon, Risako; Tsubota, Yuika; Minami, Moe; Kato, Saki; Matsunaga, Yukari; Kimura, Hiroshi; Murakami, Yuta; Fujikawa, Tetsuya; Sakurai, Ryoya; Tomimoto, Rei; Machida, Yoshiaki; Ikarashi, Nobutomo; Sugiyama, Kiyoshi

2018-01-06

While irinotecan (CPT-11) has a potent anti-cancer effect, it also causes serious diarrhea as an adverse reaction. In this study, we analyzed the pathogenic mechanism of CPT-11-induced delayed diarrhea by focusing on water channel aquaporin-3 (AQP3) in the colon. When rats received CPT-11, the expression level of AQP3 was reduced during severe diarrhea. It was found that the expression levels of inflammatory cytokines and the loss of crypt cells were increased in the colon when CPT-11 was administered. When celecoxib, an anti-inflammatory drug, was concomitantly administered, both the diarrhea and the reduced expression of AQP3 induced by CPT-11 were suppressed. The inflammation in the rat colon during diarrhea was caused via activated macrophage by CPT-11. These results showed that when CPT-11 is administered, the expression level of AQP3 in the colon is reduced, resulting in delayed diarrhea by preventing water transport from the intestinal tract. It was also suggested that the reduced expression of AQP3 might be due to the inflammation that occurs following the loss of colonic crypt cells and to the damage caused by the direct activation of macrophages by CPT-11. Therefore, it was considered that anti-inflammatory drugs that suppress the reduction of AQP3 expression could prevent CPT-11-induced delayed diarrhea.

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

Evaluation of cone penetration testing (CPT) for use with transportation projects.

DOT National Transportation Integrated Search

2011-04-01

Cone Penetration Testing (CPT) has many advantages as a means for subsurface investigation. CPT consists of pushing a steel : cone into the ground and recording the penetration resistance using sensors. Pore pressure, shear wave velocity and other : ...

Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy

PubMed Central

Tan, Zheqiong; Xiao, Lanbo; Tang, Min; Bai, Fang; Li, Jiangjiang; Li, Liling; Shi, Feng; Li, Namei; Li, Yueshuo; Du, Qianqian; Lu, Jingchen; Weng, Xinxian; Yi, Wei; Zhang, Hanwen; Fan, Jia; Zhou, Jian; Gao, Qiang; Onuchic, José N.; Bode, Ann M.; Luo, Xiangjian; Cao, Ya

2018-01-01

Nasopharyngeal carcinoma (NPC) has a particularly high prevalence in southern China, southeastern Asia and northern Africa. Radiation resistance remains a serious obstacle to successful treatment in NPC. This study aimed to explore the metabolic feature of radiation-resistant NPC cells and identify new molecular-targeted agents to improve the therapeutic effects of radiotherapy in NPC. Methods: Radiation-responsive and radiation-resistant NPC cells were used as the model system in vitro and in vivo. Metabolomics approach was used to illustrate the global metabolic changes. 13C isotopomer tracing experiment and Seahorse XF analysis were undertaken to determine the activity of fatty acid oxidation (FAO). qRT-PCR was performed to evaluate the expression of essential FAO genes including CPT1A. NPC tumor tissue microarray was used to investigate the prognostic role of CPT1A. Either RNA interference or pharmacological blockade by Etomoxir were used to inhibit CPT1A. Radiation resistance was evaluated by colony formation assay. Mitochondrial membrane potential, apoptosis and neutral lipid content were measured by flow cytometry analysis using JC-1, Annexin V and LipidTOX Red probe respectively. Molecular markers of mitochondrial apoptosis were detected by western blot. Xenografts were treated with Etomoxir, radiation, or a combination of Etomoxir and radiation. Mitochondrial apoptosis and lipid droplets content of tumor tissues were detected by cleaved caspase 9 and Oil Red O staining respectively. Liquid chromatography coupled with tandem mass spectrometry approach was used to identify CPT1A-binding proteins. The interaction of CPT1A and Rab14 were detected by immunoprecipitation, immunofluorescence and in situ proximity ligation analysis. Fragment docking and direct coupling combined computational protein-protein interaction prediction method were used to predict the binding interface. Fatty acid trafficking was measured by pulse-chase assay using BODIPY C16 and Mito

Lorentz and CPT Tests with Atoms

NASA Astrophysics Data System (ADS)

Vargas Silva, Arnaldo J.

The prospects for using atomic-spectroscopy experiments to test Lorentz and CPT symmetry are investigated. Phenomenological models for Lorentz violation studied in this work include ones with contributions from all quadratic operators for a Dirac fermion in the Lagrange density of the Standard-Model Extension (SME), without restriction on the operator mass dimension. The systems considered include atoms composed of conventional matter, antimatter, and second-generation particles. Generic expressions for the Lorentz-violating energy shifts applicable to a broad range of atomic transitions are obtained. Signals for Lorentz violation that can in principle be studied in spectroscopic experiments are identified from the theoretical corrections to the spectrum. Some of these signals include sidereal and annual variations of atomic transition frequencies measured in a laboratory on the surface of the Earth. Other possibilities include effects produced by changing the orientation of the applied magnetic field or by realizing space-based experiments. Discrepancies in the experimental values for fundamental constants and energy levels based on self-consistent predictions from the Standard Model also offer potential signals for Lorentz violation. The sensitivities of different experiments to distinct sets of coefficients for Lorentz violation are considered. Using atoms composed of different particle species allows measurements of coefficients for Lorentz violation in different fermion sectors of the SME. Experiments comparing hydrogen and antihydrogen can discriminate between coefficients for Lorentz violation that are associated with CPT-odd or CPT-even operators. Additionally, certain systems and transitions are more sensitive to nonminimal operators, while others are particularly sensitive to minimal ones.

Catharanthus alkaloids XXXII: isolation of alkaloids from Catharanthus trichophyllus roots and structure elucidation of cathaphylline.

PubMed

Cordell, G A; Farnsworth, N R

1976-03-01

Further examination of the cytotoxic alkaloid fractions of Catharanthus trichophyllus roots afforded nine alkaloids. Two of these alkaloids, lochnericine and horhammericine, are responsible for part of the cytotoxic activity. The structure elucidation of cathaphylline, a new beta-anilino acrylate derivative, is described.

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

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.

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.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamamoto, Yasuhiro; Fujita, Megumi; Koma, Hiromi

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{submore » 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}.« less

Controlling the light shift of the CPT resonance by modulation technique

NASA Astrophysics Data System (ADS)

Tsygankov, E. A.; Petropavlovsky, S. V.; Vaskovskaya, M. I.; Zibrov, S. A.; Velichansky, V. L.; Yakovlev, V. P.

2017-12-01

Motivated by recent developments in atomic frequency standards employing the effect of coherent population trapping (CPT), we propose a theoretical framework for the frequency modulation spectroscopy of the CPT resonances. Under realistic assumptions we provide simple yet non-trivial analytical formulae for the major spectroscopic signals such as the CPT resonance line and the in-phase/quadrature responses. We discuss the influence of the light shift and, in particular, derive a simple expression for the displacement of the resonance as a function of modulation index. The performance of the model is checked against numerical simulations, the agreement is good to perfect. The obtained results can be used in more general models accounting for light absorption in the thick optical medium.

Hyaluronic acid-functionalized polymeric nanoparticles for colon cancer-targeted combination chemotherapy

NASA Astrophysics Data System (ADS)

Xiao, Bo; Han, Moon Kwon; Viennois, Emilie; Wang, Lixin; Zhang, Mingzhen; Si, Xiaoying; Merlin, Didier

2015-10-01

Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments demonstrated that the introduction of HA to the NP surface endowed NPs with colon cancer-targeting capability and markedly increased cellular uptake efficiency compared with chitosan-coated NPs. Importantly, the combined delivery of CPT and CUR in one HA-functionalized NP exerted strong synergistic effects. HA-CPT/CUR-NP (1 : 1) showed the highest antitumor activity among the three HA-CPT/CUR-NPs, resulting in an extremely low combination index. Collectively, our findings indicate that this HA-CPT/CUR-NP can be exploited as an efficient formulation for colon cancer-targeted combination chemotherapy.Nanoparticle (NP)-based combination chemotherapy has been proposed as an effective strategy for achieving synergistic effects and targeted drug delivery for colon cancer therapy. Here, we fabricated a series of hyaluronic acid (HA)-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) with various weight ratios of CPT to CUR (1 : 1, 2 : 1 and 4 : 1). The resultant spherical HA-CPT/CUR-NPs had a desirable particle size (around 289 nm), relative narrow size distribution, and slightly negative zeta potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the time frame examined. Subsequent cellular uptake experiments

Intracellular inhibition of carboxylesterases by benzil: modulation of CPT-11 cytotoxicity.

PubMed

Hyatt, Janice L; Tsurkan, Lyudmila; Wierdl, Monika; Edwards, Carol C; Danks, Mary K; Potter, Philip M

2006-09-01

Carboxylesterases are ubiquitous proteins responsible for the detoxification of xenobiotics. However, these enzymes also activate prodrugs, such as the anticancer agents capecitabine and CPT-11. As a consequence, overexpression of carboxylesterases within tumor cells sensitizes these cells to CPT-11. We have recently identified two classes of carboxylesterase inhibitors based on either a benzil (diphenylethane-1,2-dione) or a benzene sulfonamide scaffold and showed that these compounds inhibit carboxylesterases with Kis in the low nanomolar range. Because both classes of inhibitors show reversible enzyme inhibition, conventional in vitro biochemical assays would not accurately reflect the in situ levels of carboxylesterase activity or inhibition. Therefore, we have developed a novel assay for the determination of intracellular carboxylesterase activity using 4-methylumbelliferone as a substrate. These studies show that benzil and a dimethylbenzil analogue efficiently enter cells and inhibit human intestinal carboxylesterase and rabbit liver carboxylesterase intracellularly. This inhibition results in reduced cytotoxicity to CPT-11 due to the lack of carboxylesterase-mediated conversion of the prodrug to SN-38. These results suggest that intracellular modulation of carboxylesterase activity with benzil or its analogues may be applied to minimize the toxicity of normal cells to CPT-11.

Lactam ergot alkaloids (ergopeptams) as predominant alkaloids in sclerotia of Claviceps purpurea from Norwegian wild grasses.

PubMed

Uhlig, Silvio; Petersen, Dirk

2008-07-01

Four major alkaloids in the extracts from sclerotia of Claviceps purpurea, picked from wild grasses, have been identified as lactam (non-cyclol) ergot alkaloids. The structural information was obtained from ion trap MS and NMR spectroscopy. The data for one of the lactam ergot alkaloids were coinciding with ergocristam [N-(lysergyl-valyl)-cyclo(phenylalanyl-prolyl)]. The structural information of two further lactam alkaloids was suggestive of either alpha- or beta-ergocryptam [N-(lysergyl-valyl)-cyclo(leucyl-prolyl) or N-(lysergyl-valyl)-cyclo(isoleucyl-prolyl)] and ergoannam [N-(lysergyl-leucyl)-cyclo(leucyl-prolyl) or N-(lysergyl-isoleucyl)-cyclo(isoleucyl-prolyl)]. The constitution of the fourth lactam ergot alkaloid corresponded to N-(lysergyl-isoleucyl)-cyclo(phenylalanyl-prolyl), a new ergopeptam, which has not been described before. Additionally, the cyclol-analogue of the new ergopeptam was detected in the extracts and has been identified on the basis of its product ion spectrum from fragmentation of [M+H](+). The study described in this paper shows that lactam ergot alkaloids may not only be minor products of ergopeptine biosynthesis, as has been suggested hitherto, but may be major biosynthetic endproducts for some ergot strains. This is also the first report demonstrating the production of an ergot alkaloid that contains isoleucine as the second amino acid, i.e. the N-(lysergyl-isoleucyl)-moiety, by parasitic, naturally growing C. purpurea. This unusual type of ergot alkaloid has so far only been found in saprophytic cultures of C. purpurea.

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.

Brassicaceae contain nortropane alkaloids.

PubMed

Brock, Andrea; Herzfeld, Tobias; Paschke, Reinhard; Koch, Marcus; Dräger, Birgit

2006-09-01

The report of cochlearine, the 3-hydroxybenzoate ester of tropine found in Cochlearia officinalis, Brassicaceae, initiated a screening for tropane alkaloids in Cochlearia species and for calystegines in further Brassicaceae. All ten Cochlearia species investigated contained cochlearine, tropine, and pseudotropine. Calystegines, nortropane alkaloids deriving from pseudotropine, were also identified in all Cochlearia species and accumulated up to 0.5% dry mass in leaves. Brassicaceae species of all major lineages of the family were analysed for calystegines. Of the 43 species included in the study, 18 accumulated calystegines of various structures. This is the first screening of Brassicaceae for products of the tropane alkaloid pathway, which is known as characteristic for plants of Solanaceae family. The identification of calystegines in all branches of the Brassicaceae family including Aethionema, a species at the basis of the family, suggests tropane alkaloids as secondary compound typical for Brassicaceae.

Ergot alkaloid transport across ruminant gastric tissues.

PubMed

Hill, N S; Thompson, F N; Stuedemann, J A; Rottinghaus, G W; Ju, H J; Dawe, D L; Hiatt, E E

2001-02-01

Ergot alkaloids cause fescue toxicosis when livestock graze endophyte-infected tall fescue. It is generally accepted that ergovaline is the toxic component of endophyte-infected tall fescue, but there is no direct evidence to support this hypothesis. The objective of this study was to examine relative and potential transport of ergoline and ergopeptine alkaloids across isolated gastric tissues in vitro. Sheep ruminal and omasal tissues were surgically removed and placed in parabiotic chambers. Equimolar concentrations of lysergic acid, lysergol, ergonovine, ergotamine, and ergocryptine were added to a Kreb's Ringer phosphate (KRP) solution on the mucosal side of the tissue. Tissue was incubated in near-physiological conditions for 240 min. Samples were taken from KRP on the serosal side of the chambers at times 0, 30, 60, 120, 180, and 240 min and analyzed for ergot alkaloids by competitive ELISA. The serosal KRP remaining after incubation was freeze-dried and the alkaloid species quantified by HPLC. The area of ruminal and omasal tissues was measured and the potential transportable alkaloids calculated by multiplying the moles of transported alkaloids per square centimeter of each tissue type by the surface area of the tissue. Studies were conducted to compare alkaloid transport in reticular, ruminal, and omasal tissues and to determine whether transport was active or passive. Ruminal tissue had greater ergot alkaloid transport potential than omasal tissue (85 vs 60 mmol) because of a larger surface area. The ruminal posterior dorsal sac had the greatest potential for alkaloid transport, but the other ruminal tissues were not different from one another. Alkaloid transport was less among reticular tissues than among ruminal tissues. Transport of alkaloids seemed to be an active process. The alkaloids with greatest transport potential were lysergic acid and lysergol. Ergopeptine alkaloids tended to pass across omasal tissues in greater quantities than across ruminal

Medical decision making: guide to improved CPT coding.

PubMed

Holt, Jim; Warsy, Ambreen; Wright, Paula

2010-04-01

The Current Procedural Terminology (CPT) coding system for office visits, which has been in use since 1995, has not been well studied, but it is generally agreed that the system contains much room for error. In fact, the available literature suggests that only slightly more than half of physicians will agree on the same CPT code for a given visit, and only 60% of professional coders will agree on the same code for a particular visit. In addition, the criteria used to assign a code are often related to the amount of written documentation. The goal of this study was to evaluate two novel methods to assess if the most appropriate CPT code is used: the level of medical decision making, or the sum of all problems mentioned by the patient during the visit. The authors-a professional coder, a residency faculty member, and a PGY-3 family medicine resident-reviewed 351 randomly selected visit notes from two residency programs in the Northeast Tennessee region for the level of documentation, the level of medical decision making, and the total number of problems addressed. The authors assigned appropriate CPT codes at each of those three levels. Substantial undercoding occurred at each of the three levels. Approximately 33% of visits were undercoded based on the written documentation. Approximately 50% of the visits were undercoded based on the level of documented medical decision making. Approximately 80% of the visits were undercoded based on the total number of problems which the patient presented during the visit. Interrater agreement was fair, and similar to that noted in other coding studies. Undercoding is not only common in a family medicine residency program but it also occurs at levels that would not be evident from a simple audit of the documentation on the visit note. Undercoding also occurs from not exploring problems mentioned by the patient and not documenting additional work that was performed. Family physicians may benefit from minor alterations in their

The concept of a marine Free-fall CPT systems revisited

NASA Astrophysics Data System (ADS)

Kopf, A.; Stegmann, S.

2005-12-01

Cone Penetration Tests (CPT) are a widely used method for the geotechnical in situ characterisation of sediments in onshore settings. In the course of enhanced use of the continental shelf and slope by humans impact, the need for time- and cost-efficient solutions in the marine realm is emerging. In order to avoid the challenges of lowering heavy gear to the seafloor for the penetration tests, free drop devices have been developed since the 1970s, however, the use of the majority of them was discontinued owing to technical difficulties in measurement and data interpretation caused by the impact. Based on those experiences, two different free-fall CPT lances were designed for the in situ measurement of strength (tip resistance, sleeve friction), pore pressure and temperature. In addition, deceleration and tilt are monitored for vertical profiling of the penetrated sediment column. Both CPT systems rely on an industry 15 cm2 piezocone with the sensors at the tip and a pressure housing containing a microprocessor at the top. The lightweight (40-100 kg), shallow water (200 m depth) lance works completely autonomous with a volatile memory and battery package, and can be deployed from any platform, even without a winch. The sturdier, deeper water (2500 m depth) system uses both power and telemetry for data transmission from the research vessel. The length and weight of either system can be varied according to the sediment stiffness and hence allow variable penetration depth (usually less than 5 m). Initial use of the CPT systems attests their efficiency and reliability in the measurement of sediment physical properties. While most of the data are collected within the first seconds of the CPT experiments, long term (pore pressure dissipation tests have also been successfully carried out for durations in excess of 6 hours. In a variety of estuarine and marine settings, our studies served objectives such as the assessment of slope stability, navigability of harbours

Models & Searches of CPT Violation: a personal, very partial, list

NASA Astrophysics Data System (ADS)

Mavromatos, Nick E.

2018-01-01

In this talk, first I motivate theoretically, and then I review the phenomenology of, some models entailing CPT Violation (CPTV). The latter is argued to be responsible for the observed matter-antimatter asymmetry in the Cosmos, and may owe its origin to either Lorentz-violating background geometries, whose effects are strong in early epochs of the Universe but very weak today, being temperature dependent in general, or to an ill-defined CPT generator in some quantum gravity models entailing decoherence of quantum matter as a result of quantum degrees of freedom in the gravity sector that are inaccessible to the low-energy observers. In particular, for the latter category of CPTV, I argue that entangled states of neutral mesons (Kaons or B-systems), of central relevance to KLOE-2 experiment, can provide smoking-gun sensitive tests or even falsify some of these models. If CPT is ill-defined one may also encounter violations of the spin-statistics theorem, with possible consequences for the Pauli Exclusion Principle, which I only briefly touch upon.

Alkaloids as Cyclooxygenase Inhibitors in Anticancer Drug Discovery.

PubMed

Hashmi, Muhammad Ali; Khan, Afsar; Farooq, Umar; Khan, Sehroon

2018-01-01

Cancer is the leading cause of death worldwide and anticancer drug discovery is a very hot area of research at present. There are various factors which control and affect cancer, out of which enzymes like cyclooxygenase-2 (COX-2) play a vital role in the growth of tumor cells. Inhibition of this enzyme is a very useful target for the prevention of various types of cancers. Alkaloids are a diverse group of naturally occurring compounds which have shown great COX-2 inhibitory activity both in vitro and in vivo. In this mini-review, we have discussed different alkaloids with COX-2 inhibitory activities and anticancer potential which may act as leads in modern anticancer drug discovery. Different classes of alkaloids including isoquinoline alkaloids, indole alkaloids, piperidine alkaloids, quinazoline alkaloids, and various miscellaneous alkaloids obtained from natural sources have been discussed in detail in this review. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

Bisindole alkaloids from Tabernaemontana corymbosa.

PubMed

Zhang, Bing-Jie; Lu, Jing-Song; Bao, Mei-Fen; Zhong, Xiu-Hong; Ni, Ling; Wu, Jing; Cai, Xiang-Hai

2018-05-11

Continued study in bioactive monoterpenoid alkaloids led to the isolation of nine undescribed alkaloids, taberyunines A-I, together with 32 known ones from the aerial parts of Tabernaemontana corymbosa Roxb. ex Wall (Apocynaceae). Among the undescribed alkaloids, taberyunines A-G and H-I were assigned to Aspidosperma-Aspidosperma and Vobasinyl-Ibogan type bisindoles, respectively. Their structures were determined by NMR spectra, MS data and X-ray diffraction. Taberyunine B showed significant cytotoxicity against three cancer cell lines. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effects of organic solvents on drug incorporation into polymeric carriers and morphological analyses of drug-incorporated polymeric micelles.

PubMed

Harada, Yoshiko; Yamamoto, Tatsuhiro; Sakai, Masaru; Saiki, Toshiharu; Kawano, Kumi; Maitani, Yoshie; Yokoyama, Masayuki

2011-02-14

We incorporated an anticancer agent, camptothecin (CPT), into polymeric micelle carriers by using two different solvents (TFE and chloroform) in the solvent-evaporation drug incorporation process. We observed significant differences in the drug-incorporation behaviors, in the morphologies of the incorporated drug and the polymeric micelles, and in the pharmacokinetic behaviors between the two solvents' cases. In particular, the CPT-incorporated polymeric micelles prepared with TFE as the incorporation solvent exhibited more stable circulation in blood than those prepared with chloroform. This contrast indicates a novel technological perspective regarding the drug incorporation into polymeric micelle carriers. Morphological analyses of the inner core have revealed the presence of the directed alignment of the CPT molecules and CPT crystals in the micelle inner core. This is the first report of the morphologies of the drug incorporated into the polymeric micelle inner cores. We believe these analyses are very important for further pharmaceutical developments of polymeric micelle drug-carrier systems. Copyright © 2010 Elsevier B.V. All rights reserved.

Resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin.

PubMed

Zunino, Susan J; Storms, David H

2017-08-01

Resveratrol has been reported to inhibit or induce DNA damage, depending upon the type of cell and the experimental conditions. Dietary resveratrol is present in the body predominantly as metabolites and limited data is available concerning the activities of these metabolic products. In the present study, physiologically obtainable levels of the resveratrol metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide and resveratrol-3-O-sulfate were evaluated for their ability to protect Jurkat T cells against DNA damage induced by the topoisomerase I inhibitors camptothecin and topotecan. The cells were pretreated for 24 h with 10 µM resveratrol aglycone or each resveratrol metabolite prior to the induction of DNA damage with camptothecin or topotecan. In separate experiments, the cells were co-treated with resveratrol or its metabolites, and a topoisomerase I inhibitor. The detection of histone 2AX phosphorylation and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) were used to determine DNA damage, and apoptosis was measured using an antibody against cleaved poly ADP-ribose polymerase. It was identified that pretreatment of the cells with resveratrol-3-O-glucuronide and resveratrol-4'-O-glucuronide reduced the mean fluorescence intensity of staining for DNA strand breaks following treatment with camptothecin, while the percentage of cells undergoing apoptosis was unchanged. However, pretreatment of the cells with resveratrol aglycone increased the DNA damage and apoptosis induced by the drugs. These results suggest that the glucuronide metabolites of resveratrol partially protected the cells from DNA damage, but did not influence the induction of cell death by camptothecin and topotecan. These data suggest that resveratrol aglycone treatment may be beneficial for treating types of cancer that have direct contact with resveratrol prior to its metabolism, including gastrointestinal cancers, which are routinely treated with

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.

Mitochondrial Carnitine Palmitoyltransferase 1a (CPT1a) Is Part of an Outer Membrane Fatty Acid Transfer Complex*

PubMed Central

Lee, Kwangwon; Kerner, Janos; Hoppel, Charles L.

2011-01-01

CPT1a (carnitine palmitoyltransferase 1a) in the liver mitochondrial outer membrane (MOM) catalyzes the primary regulated step in overall mitochondrial fatty acid oxidation. It has been suggested that the fundamental unit of CPT1a exists as a trimer, which, under native conditions, could form a dimer of the trimers, creating a hexamer channel for acylcarnitine translocation. To examine the state of CPT1a in the MOM, we employed a combined approach of sizing by mass and isolation using an immunological method. Blue native electrophoresis followed by detection with immunoblotting and mass spectrometry identified large molecular mass complexes that contained not only CPT1a but also long chain acyl-CoA synthetase (ACSL) and the voltage-dependent anion channel (VDAC). Immunoprecipitation with antisera against the proteins revealed a strong interaction between the three proteins. Immobilized CPT1a-specific antibodies immunocaptured not only CPT1a but also ACSL and VDAC, further strengthening findings with blue native electrophoresis and immunoprecipitation. This study shows strong protein-protein interaction between CPT1a, ACSL, and VDAC. We propose that this complex transfers activated fatty acids through the MOM. PMID:21622568

Biosynthetic pathways of ergot alkaloids.

PubMed

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

2014-12-10

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.

Models and (some) Searches for CPT Violation: From Early Universe to the Present Era

NASA Astrophysics Data System (ADS)

Mavromatos, Nick E.

2017-07-01

In the talk, I review theoretical models, inspired by quantum gravity, that may violate CPT symmetry. The amount of violation today (which is constrained severely by a plethora of experiments that I will not describe due to lack of space) need not be the same with the one that occurred in the Early Universe,. In certain models, one can obtain a precise temperature dependence of CPT violating effects, which is such that these effects are significant during the radiation era of the Universe, but are damped quickly so that they do not to affect nucleosynthesis and are negligible in the present epoch (that is, beyond experimental detection with the current experimental sensitivity). The CPT Violation (CPTV) in these models may arise from special properties of the background over which the fields of the model are propagating upon and be responsible for the generation of a matter-antimatter asymmetry, where any CP violation effects could only assist in the creation of the asymmetry, the dominant effect being CPTV. However, there are cases, where the CPTV arises as a consequence of an ill-defined CPT operator due to decoherence as a result of quantum gravity environmental degrees of freedom, inaccessible to a low-energy observer. I also discuss briefly the current-era phenomenology of some of the above models; in particular, for the ones involving decoherence-induced CPT violation, I argue that entangled states of neutral mesons (Kaons or B-systems) can provide smoking-gun sensitive tests or even falsify some of these models. If CPT is ill-defined one may also encounter violations of the spin-statistics theorem, with possible consequences for the Pauli Exclusion Principle.

Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy

DTIC Science & Technology

2013-09-01

lysosomes, the amides quickly hydrolyzed and regenerated LPEI. LPEI is known to be able to rupture lysosomes via the “proton- sponge ” effect13...clinics for intravenous drug delivery. Unfortunately, amphiphilic copolymers form rod-like morphology only within very narrow composition ranges...polylysine-camptothecin (PEG-xCPT) conjugates into biodegradable nanospheres or nanorods with high drug loading: The formation of the morphologies was

beta-Phenylethylamines and the isoquinoline alkaloids.

PubMed

Bentley, Kenneth W

2005-04-01

This review covers beta-phenylethylamines and isoquinoline alkaloids derived from them, including further products of oxidation, condensation with formaldehyde and rearrangement, some of which do not contain as isoquinoline system, together with napthylisoquinoline alkaloids, which have a different biogenetic origin. The occurrence of the alkaloids with the structures of new bases, together with their reactions and syntheses, are reported. The literature from July 2003 to June 2004 is reviewed, with 145 references cited.

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

Resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin

PubMed Central

Zunino, Susan J.; Storms, David H.

2017-01-01

Resveratrol has been reported to inhibit or induce DNA damage, depending upon the type of cell and the experimental conditions. Dietary resveratrol is present in the body predominantly as metabolites and limited data is available concerning the activities of these metabolic products. In the present study, physiologically obtainable levels of the resveratrol metabolites resveratrol-3-O-glucuronide, resveratrol-4′-O-glucuronide and resveratrol-3-O-sulfate were evaluated for their ability to protect Jurkat T cells against DNA damage induced by the topoisomerase I inhibitors camptothecin and topotecan. The cells were pretreated for 24 h with 10 µM resveratrol aglycone or each resveratrol metabolite prior to the induction of DNA damage with camptothecin or topotecan. In separate experiments, the cells were co-treated with resveratrol or its metabolites, and a topoisomerase I inhibitor. The detection of histone 2AX phosphorylation and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) were used to determine DNA damage, and apoptosis was measured using an antibody against cleaved poly ADP-ribose polymerase. It was identified that pretreatment of the cells with resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide reduced the mean fluorescence intensity of staining for DNA strand breaks following treatment with camptothecin, while the percentage of cells undergoing apoptosis was unchanged. However, pretreatment of the cells with resveratrol aglycone increased the DNA damage and apoptosis induced by the drugs. These results suggest that the glucuronide metabolites of resveratrol partially protected the cells from DNA damage, but did not influence the induction of cell death by camptothecin and topotecan. These data suggest that resveratrol aglycone treatment may be beneficial for treating types of cancer that have direct contact with resveratrol prior to its metabolism, including gastrointestinal cancers, which are routinely treated with

Piperidine alkaloids: human and food animal teratogens.

PubMed

Green, Benedict T; Lee, Stephen T; Panter, Kip E; Brown, David R

2012-06-01

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 teratogenic piperidine alkaloids include poison hemlock (Conium maculatum), lupine (Lupinus spp.), and tobacco (Nicotiana tabacum) [including wild tree tobacco (Nicotiana glauca)]. There is abundant epidemiological evidence in humans that link maternal tobacco use with a high incidence of oral clefting in newborns; this association may be partly attributable to the presence of piperidine alkaloids in tobacco products. In this review, we summarize the evidence for piperidine alkaloids that act as teratogens in livestock, piperidine alkaloid structure-activity relationships and their potential implications for human health. Copyright © 2012 Elsevier Ltd. All rights reserved.

Beta-phenylethylamines and the isoquinoline alkaloids.

PubMed

Bentley, Kenneth W

2003-06-01

This review covers beta-phenylethylamines and isoquinoline alkaloids and compounds derived from them, including further products of oxidation, condensation with formaldehyde and rearrangement, some of which do not contain an isoquinoline system, together with naphthylisoquinoline alkaloids, which have a different biogenetic origin. The occurrence of the alkaloids, with the structures of new bases, together with their reactions, syntheses and biological activities are reported. The literature from July 2001 to June 2002 is reviewed, with 581 references cited.

Lorentz- and CPT-symmetry studies in subatomic physics

NASA Astrophysics Data System (ADS)

Lehnert, Ralf

2016-12-01

Subatomic systems provide an exquisite test bench for spacetime symmetries. This work motivates such measurements, reviews the effective field theory test framework for the description of Lorentz and CPT violation, and employs this framework to study the phenomenology of spacetime-symmetry breaking in various subatomic systems.

Four alkaloids from Annona cherimola.

PubMed

Chen, C Y; Chang, F R; Pan, W B; Wu, Y C

2001-04-01

Four alkaloids, annocherine A, annocherine B, cherianoine, and romucosine H, along with one known alkaloid, artabonatine B, were isolated from the MeOH extract of the stems of Annona cherimola. Their structures were identified on the basis of both analysis of their spectral data and from chemical evidence.

Ergot Alkaloids of the Family Clavicipitaceae.

PubMed

Florea, Simona; Panaccione, Daniel G; Schardl, Christopher L

2017-05-01

Ergot alkaloids are highly diverse in structure, exhibit diverse effects on animals, and are produced by diverse fungi in the phylum Ascomycota, including pathogens and mutualistic symbionts of plants. These mycotoxins are best known from the fungal family Clavicipitaceae and are named for the ergot fungi that, through millennia, have contaminated grains and caused mass poisonings, with effects ranging from dry gangrene to convulsions and death. However, they are also useful sources of pharmaceuticals for a variety of medical purposes. More than a half-century of research has brought us extensive knowledge of ergot-alkaloid biosynthetic pathways from common early steps to several taxon-specific branches. Furthermore, a recent flurry of genome sequencing has revealed the genomic processes underlying ergot-alkaloid diversification. In this review, we discuss the evolution of ergot-alkaloid biosynthesis genes and gene clusters, including roles of gene recruitment, duplication and neofunctionalization, as well as gene loss, in diversifying structures of clavines, lysergic acid amides, and complex ergopeptines. Also reviewed are prospects for manipulating ergot-alkaloid profiles to enhance suitability of endophytes for forage grasses.

Ergot Alkaloids of the Family Clavicipitaceae

PubMed Central

Florea, Simona; Panaccione, Daniel G.; Schardl, Christopher L.

2017-01-01

Ergot alkaloids are highly diverse in structure, exhibit diverse effects on animals, and are produced by diverse fungi in the phylum Ascomycota, including pathogens and mutualistic symbionts of plants. These mycotoxins are best known from the fungal family Clavicipitaceae and are named for the ergot fungi that, through millennia, have contaminated grains and caused mass poisonings, with effects ranging from dry gangrene to convulsions and death. However, they are also useful sources of pharmaceuticals for a variety of medical purposes. More than a half-century of research has brought us extensive knowledge of ergot-alkaloid biosynthetic pathways from common early steps to several taxon-specific branches. Furthermore, a recent flurry of genome sequencing has revealed the genomic processes underlying ergot-alkaloid diversification. In this review, we discuss the evolution of ergot-alkaloid biosynthesis genes and gene clusters, including roles of gene recruitment, duplication and neofunctionalization, as well as gene loss, in diversifying structures of clavines, lysergic acid amides, and complex ergopeptines. Also reviewed are prospects for manipulating ergot-alkaloid profiles to enhance suitability of endophytes for forage grasses. PMID:28168931

Tipin functions in the protection against topoisomerase I inhibitor.

PubMed

Hosono, Yoshifumi; Abe, Takuya; Higuchi, Masato; Kajii, Kosa; Sakuraba, Shuichi; Tada, Shusuke; Enomoto, Takemi; Seki, Masayuki

2014-04-18

The replication fork temporarily stalls when encountering an obstacle on the DNA, and replication resumes after the barrier is removed. Simultaneously, activation of the replication checkpoint delays the progression of S phase and inhibits late origin firing. Camptothecin (CPT), a topoisomerase I (Top1) inhibitor, acts as a DNA replication barrier by inducing the covalent retention of Top1 on DNA. The Timeless-Tipin complex, a component of the replication fork machinery, plays a role in replication checkpoint activation and stabilization of the replication fork. However, the role of the Timeless-Tipin complex in overcoming the CPT-induced replication block remains elusive. Here, we generated viable TIPIN gene knock-out (KO) DT40 cells showing delayed S phase progression and increased cell death. TIPIN KO cells were hypersensitive to CPT. However, homologous recombination and replication checkpoint were activated normally, whereas DNA synthesis activity was markedly decreased in CPT-treated TIPIN KO cells. Proteasome-dependent degradation of chromatin-bound Top1 was induced in TIPIN KO cells upon CPT treatment, and pretreatment with aphidicolin, a DNA polymerase inhibitor, suppressed both CPT sensitivity and Top1 degradation. Taken together, our data indicate that replication forks formed without Tipin may collide at a high rate with Top1 retained on DNA by CPT treatment, leading to CPT hypersensitivity and Top1 degradation in TIPIN KO cells.

Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis.

PubMed

Dai, Jianye; Liang, Kai; Zhao, Shan; Jia, Wentong; Liu, Yuan; Wu, Hongkun; Lv, Jia; Cao, Chen; Chen, Tao; Zhuang, Shentian; Hou, Xiaomeng; Zhou, Shijie; Zhang, Xiannian; Chen, Xiao-Wei; Huang, Yanyi; Xiao, Rui-Ping; Wang, Yan-Ling; Luo, Tuoping; Xiao, Junyu; Wang, Chu

2018-06-11

Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis , has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.

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. Copyright © 2014. Published by Elsevier B.V.

Alkaloids from Isopyrum thalictroides L.

PubMed

Istatkova, Ralitsa; Philipov, Stefan

2004-06-01

Two new aporphine-benzylisoquinoline alkaloids thaliphine and isothaliphine with a new type of ether bridge were isolated from the roots and rhyzomes of Isopyrum thalictroides L. (Ranunculaceae). Their structures were established by physical and spectral analysis. The known alkaloid N-methylglaucine was isolated for the first time from a plant of the family Ranunculaceae.

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

Secondary and tertiary isoquinoline alkaloids from Xylopia parviflora.

PubMed

Nishiyama, Yumi; Moriyasu, Masataka; Ichimaru, Momoyo; Iwasa, Kinuko; Kato, Atsushi; Mathenge, Simon G; Chalo Mutiso, Patrick B; Juma, Francis D

2006-12-01

From the secondary and tertiary alkaloidal fractions of the root and the bark of Xylopia parviflora (Annonaceae), the isoquinoline alkaloids, 10,11-dihydroxy-1,2-dimethoxynoraporphine and parvinine were isolated, along with 39 known alkaloids. Their structures were determined on the basis of analysis of spectroscopic data.

CPT Special Report: Survey of Ph.D. Programs in Chemistry.

ERIC Educational Resources Information Center

Journal of Chemical Education, 1997

1997-01-01

Presents preliminary results from a survey taken by the American Chemical Society (ACS) Committee on Professional Training (CPT) to determine the current practices among 155 Ph.D. programs in chemistry. (DKM)

Fluorescent supramolecular micelles for imaging-guided cancer therapy

NASA Astrophysics Data System (ADS)

Sun, Mengmeng; Yin, Wenyan; Dong, Xinghua; Yang, Wantai; Zhao, Yuliang; Yin, Meizhen

2016-02-01

A novel smart fluorescent drug delivery system composed of a perylene diimide (PDI) core and block copolymer poly(d,l-lactide)-b-poly(ethyl ethylene phosphate) is developed and named as PDI-star-(PLA-b-PEEP)8. The biodegradable PDI-star-(PLA-b-PEEP)8 is a unimolecular micelle and can self-assemble into supramolecular micelles, called as fluorescent supramolecular micelles (FSMs), in aqueous media. An insoluble drug camptothecin (CPT) can be effectively loaded into the FSMs and exhibits pH-responsive release. Moreover, the FSMs with good biocompatibility can also be employed as a remarkable fluorescent probe for cell labelling because the maximum emission of PDI is beneficial for bio-imaging. The flow cytometry and confocal laser scanning microscopy analysis demonstrate that the micelles are easily endocytosed by cancer cells. In vitro and in vivo tumor growth-inhibitory studies reveal a better therapeutic effect of FSMs after CPT encapsulation when compared with the free CPT drug. The multifunctional FSM nanomedicine platform as a nanovehicle has great potential for fluorescence imaging-guided cancer therapy.A novel smart fluorescent drug delivery system composed of a perylene diimide (PDI) core and block copolymer poly(d,l-lactide)-b-poly(ethyl ethylene phosphate) is developed and named as PDI-star-(PLA-b-PEEP)8. The biodegradable PDI-star-(PLA-b-PEEP)8 is a unimolecular micelle and can self-assemble into supramolecular micelles, called as fluorescent supramolecular micelles (FSMs), in aqueous media. An insoluble drug camptothecin (CPT) can be effectively loaded into the FSMs and exhibits pH-responsive release. Moreover, the FSMs with good biocompatibility can also be employed as a remarkable fluorescent probe for cell labelling because the maximum emission of PDI is beneficial for bio-imaging. The flow cytometry and confocal laser scanning microscopy analysis demonstrate that the micelles are easily endocytosed by cancer cells. In vitro and in vivo tumor growth

Liquefaction assessment based on combined use of CPT and shear wave velocity measurements

NASA Astrophysics Data System (ADS)

Bán, Zoltán; Mahler, András; Győri, Erzsébet

2017-04-01

Soil liquefaction is one of the most devastating secondary effects of earthquakes and can cause significant damage in built infrastructure. For this reason liquefaction hazard shall be considered in all regions where moderate-to-high seismic activity encounters with saturated, loose, granular soil deposits. Several approaches exist to take into account this hazard, from which the in-situ test based empirical methods are the most commonly used in practice. These methods are generally based on the results of CPT, SPT or shear wave velocity measurements. In more complex or high risk projects CPT and VS measurement are often performed at the same location commonly in the form of seismic CPT. Furthermore, VS profile determined by surface wave methods can also supplement the standard CPT measurement. However, combined use of both in-situ indices in one single empirical method is limited. For this reason, the goal of this research was to develop such an empirical method within the framework of simplified empirical procedures where the results of CPT and VS measurements are used in parallel and can supplement each other. The combination of two in-situ indices, a small strain property measurement with a large strain measurement, can reduce uncertainty of empirical methods. In the first step by careful reviewing of the already existing liquefaction case history databases, sites were selected where the records of both CPT and VS measurement are available. After implementing the necessary corrections on the gathered 98 case histories with respect to fines content, overburden pressure and magnitude, a logistic regression was performed to obtain the probability contours of liquefaction occurrence. Logistic regression is often used to explore the relationship between a binary response and a set of explanatory variables. The occurrence or absence of liquefaction can be considered as binary outcome and the equivalent clean sand value of normalized overburden corrected cone tip

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.

Study and Optimization of CPT Resonance Parameters in 87 Rb/Ar/Ne Microcells Aimed for Application in Metrology

NASA Astrophysics Data System (ADS)

Masian, Y.; Sivak, A.; Sevostianov, D.; Vassiliev, V.; Velichansky, V.

The paper shows the presents results of studies of small-size rubidium cells with argon and neon buffer gases, produced by a patent pended technique of laser welding [Fishman et al. (2014)]. Cells were designed for miniature frequency standard. Temperature dependence of the frequency of the coherent population trapping (CPT) resonance was measured and used to optimize the ratio of partial pressures of buffer gases. The influence of duration and regime of annealing on the CPT-resonance frequency drift was investigated. The parameters of the FM modulation of laser current for two cases which correspond to the highest amplitude of CPT resonance and to the smallest light shifts of the resonance frequency were determined. The temperature dependences of the CPT resonance frequency were found to be surprisingly different in the two cases. A non-linear dependence of CPT resonance frequency on the temperature of the cell with the two extremes was revealed for one of these cases.

Testing CPT Symmetry with Current and Future CMB Measurements

NASA Astrophysics Data System (ADS)

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

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}_cs˜ p_μ A_ν \\tilde{F}μ ν , 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 \\bar{α } = -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 [Δ {α }({\\hat{n}})] 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 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 \\bar{α } and Δ {α }({\\hat{n}}). Benefited from the high precision of Planck data, the constraints of the rotation angle can be significantly improved.

Comparison of a specific HPLC determination of toxic aconite alkaloids in processed Radix aconiti with a titration method of total alkaloids.

PubMed

Csupor, Dezso; Borcsa, Botond; Heydel, Barbara; Hohmann, Judit; Zupkó, István; Ma, Yan; Widowitz, Ute; Bauer, Rudolf

2011-10-01

In traditional Chinese medicine, Aconitum (Ranunculaceae) roots are only applied after processing. Nevertheless, several cases of poisoning by improperly processed aconite roots have been reported. The aim of this study was to develop a reliable analytical method to assess the amount of toxic aconite alkaloids in commercial aconite roots, and to compare this method with the commonly used total alkaloid content determination by titration. The content of mesaconitine, aconitine, and hypaconitine in 16 commercial samples of processed aconite roots was determined by an HPLC method and the total alkaloid content by indirect titration. Five samples were selected for in vivo toxicological investigation. In most of the commercial samples, toxic alkaloids were not detectable, or only traces were found. In four samples, we could detect >0.04% toxic aconite alkaloids, the highest with a content of 0.16%. The results of HPLC analysis were compared with the results obtained by titration, and no correlation was found between the two methods. The in vivo results reassured the validity of the HPLC determination. Samples with mesaconitine, aconitine, and hypaconitine content below the HPLC detection limit still contained up to 0.2% alkaloids determined by titration. Since titration of alkaloids gives no information selectively on the aconitine-type alkaloid content and toxicity of aconite roots this method is not appropriate for safety assessment. The HPLC method developed by us provides a quick and reliable assessment of toxicity and should be considered as a purity test in pharmacopoeia monographs.

Bioactive cinchona alkaloids from Remijia peruviana.

PubMed

Ruiz-Mesia, Lastenia; Ruiz-Mesía, Wilfredo; Reina, Matías; Martínez-Diaz, Rafael; de Inés, Concepción; Guadaño, Ana; González-Coloma, Azucena

2005-03-23

Three known Cinchona alkaloids of the quinine type, quinine (1), cupreine (2), cinchonine (3), and the possible artifact cinchonine-HCl (3-HCl), along with two new ones, acetylcupreine (4) and N-ethylquinine (5), have been isolated from the bark of Remijia peruviana (Rubiaceae). Their stereochemical structures were established by high resolution NMR spectroscopy. Alkaloids 2-4 had antifeedant effects on Leptinotarsa decemlineata with varying potencies. Compound 4 was cytotoxic to both insect Sf9 and mammalian CHO cells after 48 h of incubation, while 3-HCl had stronger and selective cytotoxicity to Sf9. Quinine 1 had a moderate to low effect on Trypanosoma cruzi. Tumoral cells were also affected by these alkaloids, with 4 and 3-HCl being the most cytotoxic to all the cell lines tested. Overall, the 8R, 9S configurations, as in 3 and 3-HCl, as well as the C-6'acetylated alkaloid 4, with an 8S, 9R configuration, showed stronger biological effects.

Four new diterpenoid alkaloids from Aconitum japonicum subsp. subcuneatum.

PubMed

Yamashita, Hiroshi; Takeda, Keiko; Haraguchi, Machiko; Abe, Yuki; Kuwahara, Natsumi; Suzuki, Shota; Terui, Ayaka; Masaka, Takumi; Munakata, Naoko; Uchida, Mariko; Nunokawa, Masashi; Kaneda, Kyousuke; Goto, Masuo; Lee, Kuo-Hsiung; Wada, Koji

2018-01-01

Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. Accordingly, several diterpenoid alkaloid constituents of Aconitum and Delphinium plants as well as their derivatives exhibited cytotoxic activity against lung, prostate, nasopharyngeal, and vincristine-resistant nasopharyngeal cancer cell lines. Four new C 19 -diterpenoid alkaloids, 14-anisoyllasianine (1), 14-anisoyl-N-deethylaconine (2), N-deethylaljesaconitine A (3), and N-deethylnevadensine (4), together with 17 known C 19 - and C 20 -diterpenoid alkaloids, were isolated in a phytochemical investigation of rhizoma of Aconitum japonicum THUNB. subsp. subcuneatum (NAKAI) KADOTA. Their structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS). Eight known diterpenoid alkaloids, lipoaconitine, lipomesaconitine, aconine, nevadenine, talatisamine, nevadensine, ryosenamine, and dehydrolucidusculine, were isolated the first time from A. japonicum subsp. subcuneatum. Three of the new C 19 -diterpenoid alkaloids (1, 3, 4) and six of the known diterpenoid alkaloids were evaluated for cytotoxic activity against five human tumor cell lines.

Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia

PubMed Central

Rinaldi, Carlo; Schmidt, Thomas; Situ, Alan J.; Johnson, Janel O.; Lee, Philip R.; Chen, Ke-lian; Bott, Laura C.; Fadó, Rut; Harmison, George H.; Parodi, Sara; Grunseich, Christopher; Renvoisé, Benoît; Biesecker, Leslie G.; De Michele, Giuseppe; Santorelli, Filippo M.; Filla, Alessandro; Stevanin, Giovanni; Dürr, Alexandra; Brice, Alexis; Casals, Núria; Traynor, Bryan J.; Blackstone, Craig; Ulmer, Tobias S.; Fischbeck, Kenneth H.

2017-01-01

IMPORTANCE The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients. OBJECTIVE To identify the genetic cause for a novel form of pure autosomal dominant HSP. DESIGN, SETTING, AND PARTICIPANTS We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. MAIN OUTCOME AND MEASURE Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. RESULTS We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0

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 B 0 s 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 B 0 s → 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⊥ < 1.2more » × 10 -12 GeV and (-0.8 < ΔaT - 0.396Δa Z < 3.9) × 10 -13 GeV.« less

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abazov, V. M.

2015-10-14

We present the first search for CPT-violating effects in the mixing of B 0 s 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 B 0 s → 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⊥ < 1.2more » × 10 -12 GeV and (-0.8 < ΔaT - 0.396Δa Z < 3.9) × 10 -13 GeV.« less

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

Analgesic activity of diterpene alkaloids from Aconitum baikalensis.

PubMed

Nesterova, Yu V; Povet'yeva, T N; Suslov, N I; Zyuz'kov, G N; Pushkarskii, S V; Aksinenko, S G; Schultz, E E; Kravtsova, S S; Krapivin, A V

2014-08-01

We compared analgesic activities of individual alkaloids extracted from Baikal aconite (Aconitum baikalensis): napelline, hypaconitine, songorine, mesaconitine, 12-epinapelline N-oxide. The detected analgesic activity was comparable to that of sodium metamizole. The mechanisms of analgesia were different in diterpene alkaloids of different structure. The antinociceptive effect of atisine alkaloids (12-epinapelline N-oxide, songorine) was naloxonedependent and realized via opioid receptor modulation.

Dextran vesicular carriers for dual encapsulation of hydrophilic and hydrophobic molecules and delivery into cells.

PubMed

Pramod, P S; Takamura, Kathryn; Chaphekar, Sonali; Balasubramanian, Nagaraj; Jayakannan, M

2012-11-12

Dextran vesicular nanoscaffolds were developed based on polysaccharide and renewable resource alkyl tail for dual encapsulation of hydrophilic and hydrophobic molecules (or drugs) and delivery into cells. The roles of the hydrophobic segments on the molecular self-organization of dextran backbone into vesicles or nanoparticles were investigated in detail. Dextran vesicles were found to be a unique dual carrier in which water-soluble molecules (like Rhodamine-B, Rh-B) and polyaromatic anticancer drug (camptothecin, CPT) were selectively encapsulated in the hydrophilic core and hydrophobic layer, respectively. The dextran vesicles were capable of protecting the plasma-sensitive CPT lactone pharmacophore against the hydrolysis by 10× better than the CPT alone in PBS. The aliphatic ester linkage connecting the hydrophobic tail with dextran was found to be cleaved by esterase under physiological conditions for fast releasing of CPT or Rh-B. Cytotoxicity of the dextran vesicle and its drug conjugate were tested on mouse embryonic fibroblast cells (MEFs) using MTT assay. The dextran vesicular scaffold was found to be nontoxic to living cells. CPT loaded vesicles were found to be 2.5-fold more effective in killing fibroblasts compared to that of CPT alone in PBS. Confocal microscopic images confirmed that both Rh-B and CPT loaded vesicles to be taken up by fibroblasts compared to CPT alone, showing a distinctly perinuclear localization in cells. The custom designed dextran vesicular provides new research opportunities for dual loading and delivering of hydrophilic and hydrophobic drug molecules.

Estimation of total alkaloid in Chitrakadivati by UV-Spectrophotometer.

PubMed

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

2012-04-01

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. 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). 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.

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

Analysis and modification of ergot alkaloid profiles in fungi.

PubMed

Panaccione, Daniel G; Ryan, Katy L; Schardl, Christopher L; Florea, Simona

2012-01-01

The ergot alkaloids are a family of secondary metabolites produced by a phylogenetically discontinuous group of fungi. Various members of the family are important in agriculture, where they accumulate in grain crops or forage grasses and adversely affect humans or animals who consume them. Other ergot alkaloids have been used clinically to treat a variety of diseases. Because of their significance in agriculture and medicine, the ability to detect and quantify these alkaloids from a variety of substrates is important. The primary analytical approach for these purposes has been high performance liquid chromatography. The ability to manipulate ergot alkaloid production in fungi, by transformation-mediated approaches, has been useful for studies on the biosynthesis of these alkaloids and may have practical application in agriculture and medicine. Such modifications have been informed by comparative genomic approaches, which have provided information on the gene clusters associated with ergot alkaloid biosynthesis. Copyright © 2012 Elsevier Inc. All rights reserved.

New pyrrolizidine alkaloids from Heliotropium crassifolium.

PubMed

Farsam, H; Yassa, N; Sarkhail, P; Shafiee, A

2000-05-01

Heliotropium crassifolium Boiss, (Boraginaceae) from a population of Ilam, western region of Iran was studied for pyrrolizidine alklaoids (PAs). Four alkaloids have been identified: europine 1, europine N-oxide 2 and a new pyrrolizidine alkaloids ilamine 3 and its N-oxide 4, respectively. Their structures were elucidated by IR, 1H-NMR and EIMS data.

27 CFR 21.99 - Brucine alkaloid.

Code of Federal Regulations, 2011 CFR

2011-04-01

..., characteristic of strychnine, will be obtained. (d) Sulfate test. No white precipitate is formed that is not... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of... tetrahydrate melts at 105 °C. while the anhydrous form melts at 178 °C. (c) Strychnine test. Brucine alkaloid...

27 CFR 21.99 - Brucine alkaloid.

Code of Federal Regulations, 2012 CFR

2012-04-01

..., characteristic of strychnine, will be obtained. (d) Sulfate test. No white precipitate is formed that is not... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of... tetrahydrate melts at 105 °C. while the anhydrous form melts at 178 °C. (c) Strychnine test. Brucine alkaloid...

27 CFR 21.99 - Brucine alkaloid.

Code of Federal Regulations, 2014 CFR

2014-04-01

..., characteristic of strychnine, will be obtained. (d) Sulfate test. No white precipitate is formed that is not... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of... tetrahydrate melts at 105 °C. while the anhydrous form melts at 178 °C. (c) Strychnine test. Brucine alkaloid...

27 CFR 21.99 - Brucine alkaloid.

Code of Federal Regulations, 2013 CFR

2013-04-01

..., characteristic of strychnine, will be obtained. (d) Sulfate test. No white precipitate is formed that is not... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of... tetrahydrate melts at 105 °C. while the anhydrous form melts at 178 °C. (c) Strychnine test. Brucine alkaloid...

27 CFR 21.99 - Brucine alkaloid.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., characteristic of strychnine, will be obtained. (d) Sulfate test. No white precipitate is formed that is not... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of... tetrahydrate melts at 105 °C. while the anhydrous form melts at 178 °C. (c) Strychnine test. Brucine alkaloid...

Bioactive alkaloids produced by fungi. I. Updates on alkaloids from the species of the genera Boletus, Fusarium and psilocybe.

PubMed

Mahmood, Zafar Alam; Ahmed, Syed Waseemuddin; Azhar, Iqbal; Sualeh, Mohammad; Baig, Mirza Tasawer; Zoha, Sms

2010-07-01

Fungi, in particular, are able in common with the higher plants and bacteria, to produce metabolites, including alkaloids. Alkaloids, along with other metabolites are the most important fungal metabolites from pharmaceutical and industrial point of view. Based on this observation, the authors of this review article have tried to provide an information on the alkaloids produced by the species of genera: Boletus, Fusarium and Psilocybef from 1981-2009. Thus the review would be helpful and provides valuable information for the researchers of the same field.

The ergot alkaloid gene cluster: functional analyses and evolutionary aspects.

PubMed

Lorenz, Nicole; Haarmann, Thomas; Pazoutová, Sylvie; Jung, Manfred; Tudzynski, Paul

2009-01-01

Ergot alkaloids and their derivatives have been traditionally used as therapeutic agents in migraine, blood pressure regulation and help in childbirth and abortion. Their production in submerse culture is a long established biotechnological process. Ergot alkaloids are produced mainly by members of the genus Claviceps, with Claviceps purpurea as best investigated species concerning the biochemistry of ergot alkaloid synthesis (EAS). Genes encoding enzymes involved in EAS have been shown to be clustered; functional analyses of EAS cluster genes have allowed to assign specific functions to several gene products. Various Claviceps species differ with respect to their host specificity and their alkaloid content; comparison of the ergot alkaloid clusters in these species (and of clavine alkaloid clusters in other genera) yields interesting insights into the evolution of cluster structure. This review focuses on recently published and also yet unpublished data on the structure and evolution of the EAS gene cluster and on the function and regulation of cluster genes. These analyses have also significant biotechnological implications: the characterization of non-ribosomal peptide synthetases (NRPS) involved in the synthesis of the peptide moiety of ergopeptines opened interesting perspectives for the synthesis of ergot alkaloids; on the other hand, defined mutants could be generated producing interesting intermediates or only single peptide alkaloids (instead of the alkaloid mixtures usually produced by industrial strains).

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

Electrospun Composites of Polycaprolactone and Porous Silicon Nanoparticles for the Tunable Delivery of Small Therapeutic Molecules

PubMed Central

McInnes, Steven J. P.; Macdonald, Thomas J.; Parkin, Ivan P.; Voelcker, Nicolas H.

2018-01-01

This report describes the use of an electrospun composite of poly(ε-caprolactone) (PCL) fibers and porous silicon (pSi) nanoparticles (NPs) as an effective system for the tunable delivery of camptothecin (CPT), a small therapeutic molecule. Both materials are biodegradable, abundant, low-cost, and most importantly, have no known cytotoxic effects. The composites were treated with and without sodium hydroxide (NaOH) to investigate the wettability of the porous network for drug release and cell viability measurements. CPT release and subsequent cell viability was also investigated. We observed that the cell death rate was not only affected by the addition of our CPT carrier, pSi, but also by increasing the rate of dissolution via treatment with NaOH. This is the first example of loading pSi NPs as a therapeutics nanocarrier into electronspun PCL fibers and this system opens up new possibilities for the delivery of molecular therapeutics. PMID:29596352

Chemistry and Biology of the Pyrrole-Imidazole Alkaloids.

PubMed

Lindel, Thomas

More than a decade after our last review on the chemistry of the pyrrole-imidazole alkaloids, it was time to analyze once more the developments in that field. The comprehensive article focusses on the total syntheses of pyrrole-imidazole alkaloids that have appeared since 2005. The classic monomeric pyrrole-imidazole alkaloids have all been synthesized, sometimes primarily to demonstrate the usefulness of a new method, as in the case of the related molecules agelastatin A and cyclooroidin with more than 15 syntheses altogether. The phakellin skeleton has been made more than 10 times, too, with a focus on the target structure itself. Thus, some of the pyrrole-imidazole alkaloids are now available in gram amounts, and the supply problem has been solved. The total synthesis of the dimeric pyrrole-imidazole alkaloids is still mostly in its pioneering phase with two routes to palau'amine and massadine discovered and three routes to the axinellamines and ageliferin. In addition, the review summarizes recent discoveries regarding the biological activity of the pyrrole-imidazole alkaloids. Regarding the biosynthesis of sceptrin, a pathway is proposed that starts from nagelamide I and proceeds via two electrocyclizations and reduction. Copyright © 2017 Elsevier Inc. All rights reserved.

A new benzylisoquinoline alkaloid from Leontice altaica.

PubMed

Jenis, Janar; Nugroho, Alfarius Eko; Hashimoto, Akiyo; Deguchi, Jun; Hirasawa, Yusuke; Wong, Chin Piow; Kaneda, Toshio; Shirota, Osamu; Morita, Hiroshi

2015-02-01

A new benzylisoquinoline alkaloid, lincangenine-4-β-D-glucopyranoside (1), has been isolated from the roots of Leontice altaica, together with 5 known alkaloids. Its structure was elucidated on the basis of 1D and 2D NMR data, and chemical means.

Anticholinesterase inhibitory activity of quaternary alkaloids from Tinospora crispa.

PubMed

Yusoff, Mashitah; Hamid, Hazrulrizawati; Houghton, Peter

2014-01-20

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.

Ergot Alkaloids and their Hallucinogenic Potential in Morning Glories.

PubMed

Steiner, Ulrike; Leistner, Eckhard

2018-03-02

Naturally occurring and semisynthetic ergot alkaloids play a role in health care or as recreational drugs in Western and indigenous Mexican societies. Evidence is summarized that ergot alkaloids present in Central American Convolvulaceae like Turbina corymbosa, Ipomoea violacea , and Ipomoea asarifolia are colonized by different species of a newly described clavicipitaceous fungal genus named Periglandula . The fungi are associated with peltate glandular trichomes on the adaxial leaf surface of its host plants. The Periglandula fungi are not yet culturable in vitro but were demonstrated to have the capacity to synthesize ergot alkaloids. The alkaloids do not remain in the fungal mycelium but are translocated via the glandular trichomes into their plant host. Both fungi and host benefit from a symbiotic lifestyle. In evolutionary terms the alkaloid biosynthetic gene cluster in the Periglandula/Ipomoea symbiosis is likely to have a conserved (basic) structure while biosynthetic ergot gene clusters within the genera Claviceps and Epichloe were under ecological selection for alkaloid diversification. Georg Thieme Verlag KG Stuttgart · New York.

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.

Racemic alkaloids from the fungus Ganoderma cochlear.

PubMed

Wang, Xin-Long; Dou, Man; Luo, Qi; Cheng, Li-Zhi; Yan, Yong-Ming; Li, Rong-Tao; Cheng, Yong-Xian

2017-01-01

Seven pairs of new alkaloid enantiomers, ganocochlearines C-I (1, 3-8), and three pairs of known alkaloids were isolated from the fruiting bodies of Ganoderma cochlear. The chemical structures of new compounds were elucidated on the basis of 1D and 2D NMR data. The absolute configurations of compounds 1, 3-10 were assigned by ECD calculations. Biological activities of these isolates against renal fibrosis were accessed in rat normal or diseased renal interstitial fibroblast cells. Importantly, the plausible biosynthetic pathway for this class of alkaloids was originally proposed. Copyright © 2016 Elsevier B.V. All rights reserved.

Diterpenoid alkaloids from the roots of Aconitum brachypodum Diels.

PubMed

Yang, Li-Guo; Zhang, Ying-Jie; Xie, Jia-Ying; Xia, Wei-Jun; Zhang, Hai-Yuan; Tang, Meng-Yun; Mei, Shuang-Xi; Cui, Tao; Wang, Jing-Kun; Zhu, Zhao-Yun

2016-09-01

A new diterpenoid alkaloid, named bullatine H (1), along with 10 known diterpenoid alkaloids were isolated from the roots of Aconitum brachypodum Diels (Ranunculaceae). The structure of 1 was elucidated by analysis of its spectroscopic data. It should be noted that compound 1 is the first example with 11, 13-dioxygenated denudatine-type diterpenoid alkaloid isolated from Aconitum brachypodum.

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.

Recent patents therapeutic agents for cancer.

PubMed

Li, Xun; Xu, Wenfang

2006-06-01

Cancer is one of the most dreaded diseases with a complex pathogenesis, which threats human life greatly. Multidisciplinary scientific investigations are making best efforts to combat this disease and put to the identification of novel anticancer agents. Patent anticancer agents registered in China are therefore increasing dramatically during the past ten years, which will be reviewed briefly in this article. platinum complexes anthracycline analogs (including doxorubicin derivatives) quinoline analogs podophyllotoxins analogs taxane analogs camptothecin (CPT) analogs.

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. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Ubiquitin-Proteasome Pathway for the Repair of Topoisomerase I-DNA Covalent Complexes*S⃞

PubMed Central

Lin, Chao-Po; Ban, Yi; Lyu, Yi Lisa; Desai, Shyamal D.; Liu, Leroy F.

2008-01-01

Reversible topoisomerase I (Top1)-DNA cleavage complexes are the key DNA lesion induced by anticancer camptothecins (e.g. topotecan and irinotecan) as well as structurally perturbed DNAs (e.g. oxidatively damaged DNA, UV-irradiated DNA, alkylated DNA, uracil-substituted DNA, mismatched DNA, gapped and nicked DNA, and DNA with abasic sites). Top1 cleavage complexes arrest transcription and trigger transcription-dependent degradation of Top1, a phenomenon termed Top1 down-regulation. In the current study, we have investigated the role of Top1 down-regulation in the repair of Top1 cleavage complexes. Using quiescent (serum-starved) human WI-38 cells, camptothecin (CPT) was shown to induce Top1 down-regulation, which paralleled the induction of DNA single-strand breaks (SSBs) (assayed by comet assays) and ATM autophosphorylation (at Ser-1981). Interestingly, Top1 down-regulation, induction of DNA SSBs and ATM autophosphorylation were all abolished by the proteasome inhibitor MG132. Furthermore, studies using immunoprecipitation and dominant-negative ubiquitin mutants have suggested a specific requirement for the assembly of Lys-48-linked polyubiquitin chains for CPT-induced Top1 down-regulation. In contrast to the effect of proteasome inhibition, inactivation of PARP1 was shown to increase the amount of CPT-induced SSBs and the level of ATM autophosphorylation. Together, these results support a model in which Top1 cleavage complexes arrest transcription and activate a ubiquitin-proteasome pathway leading to the degradation of Top1 cleavage complexes. Degradation of Top1 cleavage complexes results in the exposure of Top1-concealed SSBs for repair through a PARP1-dependent process. PMID:18515798

Design of enzyme-mediated controlled release systems based on silica mesoporous supports capped with ester-glycol groups.

PubMed

Agostini, Alessandro; Mondragón, Laura; Pascual, Lluis; Aznar, Elena; Coll, Carmen; Martínez-Máñez, Ramón; Sancenón, Félix; Soto, Juan; Marcos, M Dolores; Amorós, Pedro; Costero, Ana M; Parra, Margarita; Gil, Salvador

2012-10-16

An ethylene glycol-capped hybrid material for the controlled release of molecules in the presence of esterase enzyme has been prepared. The final organic-inorganic hybrid solid S1 was synthesized by a two-step procedure. In the first step, the pores of an inorganic MCM-41 support (in the form of nanoparticles) were loaded with [Ru(bipy)(3)]Cl(2) complex, and then, in the second step, the pore outlets were functionalized with ester glycol moieties that acted as molecular caps. In the absence of an enzyme, release of the complex from aqueous suspensions of S1 at pH 8.0 is inhibited due to the steric hindrance imposed by the bulky ester glycol moieties. Upon addition of esterase enzyme, delivery of the ruthenium complex was observed due to enzymatic hydrolysis of the ester bond in the anchored ester glycol derivative, inducing the release of oligo(ethylene glycol) fragments. Hydrolysis of the ester bond results in size reduction of the appended group, therefore allowing delivery of the entrapped cargo. The S1 nanoparticles were not toxic for cells, as demonstrated by cell viability assays with HeLa and MCF-7 cell lines, and were found to be associated with lysosomes, as shown by confocal microscopy. However, when S1 nanoparticles were filled with the cytotoxic drug camptothecin (S1-CPT), S1-CPT-treated cells undergo cell death as a result of S1-CPT cell internalization and subsequent cellular enzyme-mediated hydrolysis and aperture of the molecular gate that induced the release of the camptothecin cargo. These findings point to a possible therapeutic application of these nanoparticles.

Cell-cycle-dependent three-dimensional redistribution of nuclear proteins, P 120, pKi-67, and SC 35 splicing factor, in the presence of the topoisomerase I inhibitor camptothecin.

PubMed

Elias, Emmanuel; Lalun, Nathalie; Lorenzato, Marianne; Blache, Laurent; Chelidze, Pavel; O'Donohue, Marie-Françoise; Ploton, Dominique; Bobichon, Hélène

2003-11-15

Topoisomerase I (Topo I) is mostly known for its role in DNA relaxation, which is required for duplication and transcription. Topo I acts as a protein kinase mainly directed to the mRNA splicing factor SC35. Camptothecin is one of the specific Topo I inhibitors and is effective on the two functions of the enzyme. In this study we demonstrated that treatment of KB cells with camptothecin for only 30 min induced the 3D reorganization and redistribution of three proteins involved in the nucleus machinery, P 120, pKi-67, and SC 35, and this occurred in a cell cycle-dependent manner. Our data were obtained from confocal microscopic studies after immunolabeling, 3D reconstruction, and measurement of the nuclear components volumes. In the presence of camptothecin, P 120, which occupied the nucleolar volume, lost its reticulation and pKi-67 was redistributed within the nucleoplasm and even into the cytoplasm. Finally, for SC 35 the fusion of its dots into bigger volumes was observed specifically during the G1 phase. Variations of volumes were also observed for the nucleolus and for the nucleus. These results pointed out that, depending on the cell cycle phase, Topo I functions were selective toward the three different proteins.

Cytotoxicity and accumulation of ergot alkaloids in human primary cells.

PubMed

Mulac, Dennis; Humpf, Hans-Ulrich

2011-04-11

Ergot alkaloids are secondary metabolites produced by fungi of the species Claviceps. Toxic effects after consumption of contaminated grains are described since mediaeval times. Of the more than 40 known ergot alkaloids six are found predominantly. These are ergotamine, ergocornine, ergocryptine, ergocristine, ergosine and ergometrine, along with their corresponding isomeric forms (-inine-forms). Toxic effects are known to be induced by an interaction of the ergot alkaloids as neurotransmitters, like dopamine or serotonin. Nevertheless data concerning cytotoxic effects are missing and therefore a screening of the six main ergot alkaloids was performed in human primary cells in order to evaluate the toxic potential. As it is well known that ergot alkaloids isomerize easily the stability was tested in the cell medium. Based on these results factors were calculated to correct the used concentration values to the biologically active lysergic (-ine) form. These factors range from 1.4 for the most stable compound ergometrine to 5.0 for the most unstable ergot alkaloid ergocristine. With these factors, reflecting the instability, several controverse literature data concerning the toxicity could be explained. To evaluate the cytotoxic effects of ergot alkaloids, human cells in primary culture were used. These cells remain unchanged in contrast to cell lines and the data allow a better comparison to the in vivo situation than using immortalized cell lines. To characterize the effects on primary cells, renal proximal tubule epithelial cells (RPTEC) and normal human astrocytes (NHA) were used. The parameters necrosis (LDH-release) and apoptosis (caspase-3-activation, DNA condensation and fragmentation) were distinguished. The results show that depending on the individual structure of the peptide ergot alkaloids the toxic properties change. While ergometrine as a lysergic acid amide did not show any effect, the peptide ergot alkaloids revealed a different toxic potential. Of

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

Genetic variation of piperidine alkaloids in Pinus ponderosa: a common garden study.

PubMed

Gerson, Elizabeth A; Kelsey, Rick G; St Clair, J Bradley

2009-02-01

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. 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. 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. 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 secondary metabolism in ponderosa pine. The theoretical

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

8-pCPT-cGMP prevents mitochondrial depolarization and improves the outcome of steatotic partial liver transplantation

PubMed Central

Liu, Qinlong; Rehman, Hasibur; Krishnasamy, Yasodha; Lemasters, John J; Zhong, Zhi

2017-01-01

Permeant cGMP analogs prevent the mitochondria permeability transition (MPT) in vitro. In this study, we explored whether 8-pCPT-cGMP prevents the MPT and decreases post-transplant damage to fatty partial liver grafts (FPG) in vivo. Rats were fed a control or high-fat, high-fructose diet for 2-week. Lean and fatty liver explants were reduced in size ex vivo to ~35% and stored in the University of Wisconsin solution with and without 8-pCPT-cGMP (300 µM) for 2 h. After transplantation, alanine aminotransferase release (indicator of hepatocellular injury), hyperbilirubinemia (indicator of poor liver function), and cell death were all higher in FPG than in lean partial grafts (LPG). Liver regeneration increased in LPG but was suppressed in FPG. 8-pCPT-cGMP blunted graft injury, improved liver regeneration and function, and increased survival of FPG. Hepatic mitochondrial depolarization detected by intravital multiphoton microscopy of rhodamine 123 in living rats was ~3.5-fold higher in FPG than in LPG. 8-pCPT-cGMP decreased mitochondrial depolarization in FPG almost to the level of LPG. Activation of mammalian target of rapamycin (mTOR), an energy sensitive kinase that stimulates cell proliferation and growth, and p70S6 kinase, a downstream signaling molecule of mTOR, was increased in LPG but suppressed in FPG. 8-pCPT-cGMP restored the activity of mTOR and p70S6 kinase in FPG. 8-pCPT-cGMP also increased activation of cAMP response element-binding protein (CREB) and expression of cyclins D1 and E in FPG. Non-alcoholic steatosis increases injury and suppresses regeneration after partial liver transplantation, at least in part, due to more severe mitochondrial dysfunction. Protection of mitochondria with a cGMP analog effectively improves outcomes of FPG transplantation. PMID:28694919

Alkaloid profiles of Mimosa tenuiflora and associated methods of analysis

USDA-ARS?s Scientific Manuscript database

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...

Optimization of yeast-based production of medicinal protoberberine alkaloids.

PubMed

Galanie, Stephanie; Smolke, Christina D

2015-09-16

Protoberberine alkaloids are bioactive molecules abundant in plant preparations for traditional medicines. Yeast engineered to express biosynthetic pathways for fermentative production of these compounds will further enable investigation of the medicinal properties of these molecules and development of alkaloid-based drugs with improved efficacy and safety. Here, we describe the optimization of a biosynthetic pathway in Saccharomyces cerevisiae for conversion of rac-norlaudanosoline to the protoberberine alkaloid (S)-canadine. This yeast strain is engineered to express seven heterologous enzymes, resulting in protoberberine alkaloid production from a simple benzylisoquinoline alkaloid precursor. The seven enzymes include three membrane-bound enzymes: the flavin-dependent oxidase berberine bridge enzyme, the cytochrome P450 canadine synthase, and a cytochrome P450 reductase. A number of strategies were implemented to improve flux through the pathway, including enzyme variant screening, genetic copy number variation, and culture optimization, that led to an over 70-fold increase in canadine titer up to 1.8 mg/L. Increased canadine titers enable extension of the pathway to produce berberine, a major constituent of several traditional medicines, for the first time in a microbial host. We also demonstrate that this strain is viable at pilot scale. By applying metabolic engineering and synthetic biology strategies for increased conversion of simple benzylisoquinoline alkaloids to complex protoberberine alkaloids, this work will facilitate chemoenzymatic synthesis or de novo biosynthesis of these and other high-value compounds using a microbial cell factory.

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

An efficient probe of the cosmological CPT violation

NASA Astrophysics Data System (ADS)

Zhao, Gong-Bo; Wang, Yuting; Xia, Jun-Qing; Li, Mingzhe; Zhang, Xinmin

2015-07-01

We develop an efficient method based on the linear regression algorithm to probe the cosmological CPT violation using the CMB polarisation data. We validate this method using simulated CMB data and apply it to recent CMB observations. We find that a combined data sample of BICEP1 and BOOMERanG 2003 favours a nonzero isotropic rotation angle at 2.3σ confidence level, i.e., bar alpha=-3.3o±1.4o (68% CL) with systematics included.

An ergot alkaloid biosynthesis gene and clustered hypothetical genes from Aspergillus fumigatus.

PubMed

Coyle, Christine M; Panaccione, Daniel G

2005-06-01

The ergot alkaloids are a family of indole-derived mycotoxins with a variety of significant biological activities. Aspergillus fumigatus, a common airborne fungus and opportunistic human pathogen, and several fungi in the relatively distant taxon Clavicipitaceae (clavicipitaceous fungi) produce different sets of ergot alkaloids. The ergot alkaloids of these divergent fungi share a four-member ergoline ring but differ in the number, type, and position of the side chains. Several genes required for ergot alkaloid production are known in the clavicipitaceous fungi, and these genes are clustered in the genome of the ergot fungus Claviceps purpurea. We investigated whether the ergot alkaloids of A. fumigatus have a common biosynthetic and genetic origin with those of the clavicipitaceous fungi. A homolog of dmaW, the gene controlling the determinant step in the ergot alkaloid pathway of clavicipitaceous fungi, was identified in the A. fumigatus genome. Knockout of dmaW eliminated all known ergot alkaloids from A. fumigatus, and complementation of the mutation restored ergot alkaloid production. Clustered with dmaW in the A. fumigatus genome are sequences corresponding to five genes previously proposed to encode steps in the ergot alkaloid pathway of C. purpurea, as well as additional sequences whose deduced protein products are consistent with their involvement in the ergot alkaloid pathway. The corresponding genes have similarities in their nucleotide sequences, but the orientations and positions within the cluster of several of these genes differ. The data indicate that the ergot alkaloid biosynthetic capabilities in A. fumigatus and the clavicipitaceous fungi had a common origin.

An Ergot Alkaloid Biosynthesis Gene and Clustered Hypothetical Genes from Aspergillus fumigatus†

PubMed Central

Coyle, Christine M.; Panaccione, Daniel G.

2005-01-01

The ergot alkaloids are a family of indole-derived mycotoxins with a variety of significant biological activities. Aspergillus fumigatus, a common airborne fungus and opportunistic human pathogen, and several fungi in the relatively distant taxon Clavicipitaceae (clavicipitaceous fungi) produce different sets of ergot alkaloids. The ergot alkaloids of these divergent fungi share a four-member ergoline ring but differ in the number, type, and position of the side chains. Several genes required for ergot alkaloid production are known in the clavicipitaceous fungi, and these genes are clustered in the genome of the ergot fungus Claviceps purpurea. We investigated whether the ergot alkaloids of A. fumigatus have a common biosynthetic and genetic origin with those of the clavicipitaceous fungi. A homolog of dmaW, the gene controlling the determinant step in the ergot alkaloid pathway of clavicipitaceous fungi, was identified in the A. fumigatus genome. Knockout of dmaW eliminated all known ergot alkaloids from A. fumigatus, and complementation of the mutation restored ergot alkaloid production. Clustered with dmaW in the A. fumigatus genome are sequences corresponding to five genes previously proposed to encode steps in the ergot alkaloid pathway of C. purpurea, as well as additional sequences whose deduced protein products are consistent with their involvement in the ergot alkaloid pathway. The corresponding genes have similarities in their nucleotide sequences, but the orientations and positions within the cluster of several of these genes differ. The data indicate that the ergot alkaloid biosynthetic capabilities in A. fumigatus and the clavicipitaceous fungi had a common origin. PMID:15933009

Five New Alkaloids from the Roots of Sophora flavescens.

PubMed

Zhang, Sheng-Yuan; Li, Wen; Nie, Hua; Liao, Mei; Qiu, Bo; Yang, Ya-Li; Chen, Yan-Fen

2018-03-01

Five new quinolizidine alkaloids, including three sparteine-type alkaloids (1 - 3) and two cytisine-type alkaloids (4 and 5), along with four known ones, were isolated from the roots of Sophora flavescens. Their structures were determined by extensive spectroscopic techniques including IR, UV, NMR, and HR-ESI-MS. All the compounds were evaluated for their antibacterial activities against Staphylococcus aureus and Escherichia coli. © 2018 Wiley-VHCA AG, Zurich, Switzerland.

Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity

PubMed Central

Maples, Jill M.; Brault, Jeffrey J.; Witczak, Carol A.; Park, Sanghee; Hubal, Monica J.; Weber, Todd M.; Houmard, Joseph A.

2015-01-01

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

Prospects for testing Lorentz and CPT symmetry with antiprotons

NASA Astrophysics Data System (ADS)

Vargas, Arnaldo J.

2018-03-01

A brief overview of the prospects of testing Lorentz and CPT symmetry with antimatter experiments is presented. The models discussed are applicable to atomic spectroscopy experiments, Penning-trap experiments and gravitational tests. Comments about the sensitivity of the most recent antimatter experiments to the models reviewed here are included. This article is part of the Theo Murphy meeting issue `Antiproton physics in the ELENA era'.

New zwitterionic monoterpene indole alkaloids from Uncaria rhynchophylla.

PubMed

Guo, Qiang; Yang, Hongshuai; Liu, Xinyu; Si, Xiali; Liang, Hong; Tu, Pengfei; Zhang, Qingying

2018-01-31

Four new zwitterionic monoterpene indole alkaloids, rhynchophyllioniums A-D (1-4), together with eight known alkaloids (5-12), were isolated from the hook-bearing stems of Uncaria rhynchophylla. Their structures were elucidated by extensive spectroscopic data analysis of MS, 1D and 2D NMR, and ECD, and the zwitterionic forms and absolute configurations of 1 and 2 were unambiguously confirmed by single crystal X-ray diffraction analysis. All the isolates, including the monoterpene indole alkaloids with free C-22 carboxyl group and those with C-22 carboxyl methyl ester, were proved to be naturally coexisting in the herb by LC-MS analysis. This is the first report of monoterpene indole alkaloids that exist in the form of zwitterion. Additionally, the cytotoxic activities of all isolates against A549, HepG2, and MCF-7 cell lines are reported. Copyright © 2018 Elsevier B.V. All rights reserved.

Total alkaloid content in various fractions of Tabernaemonata sphaerocarpa Bl. (Jembirit) leaves

NASA Astrophysics Data System (ADS)

Salamah, N.; Ningsih, D. S.

2017-11-01

Tabernaemontana sphaerocarpa Bl. (Jembirit) is one of the Apocynaceae family plants containing alkaloid compound. Traditionally, it is used as an anti-inflammatory medicine. It is found to have a new bisindole alkaloid compound that shows a potent cytotoxic activity in human cancer. This study aimed to know the total alkaloid content in some fractions of ethanolic extract of T. sphaerocarpa Bl. leaf powder was extracted by maceration method in 70% ethanol solvent. Then, the extract was fractionated in a separatory funnel using water, ethyl acetate, and hexane. The total alkaloid content in each fraction was analyzed with visible spectrophotometric methods based on the reaction with Bromocresol Green (BCG). The total alkaloids in water fraction and ethyl acetate fraction were (0.0312±0.0009)% and (0.0281±0.0014)%, respectively. Meanwhile, the total alkaloid content in hexane was not detected. The statistical analysis, performed in SPSS, resulted in a significant difference between the total alkaloids in water fraction and ethyl acetate fraction. The total alkaloid in water fraction of T. sphaerocarpa Bl. was higher than the one in ethyl acetate fraction.

CPT1{alpha} over-expression increases long-chain fatty acid oxidation and reduces cell viability with incremental palmitic acid concentration in 293T cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jambor de Sousa, Ulrike L.; Koss, Michael D.; Fillies, Marion

2005-12-16

To test the cellular response to an increased fatty acid oxidation, we generated a vector for an inducible expression of the rate-limiting enzyme carnitine palmitoyl-transferase 1{alpha} (CPT1{alpha}). Human embryonic 293T kidney cells were transiently transfected and expression of the CPT1{alpha} transgene in the tet-on vector was activated with doxycycline. Fatty acid oxidation was measured by determining the conversion of supplemented, synthetic cis-10-heptadecenoic acid (C17:1n-7) to C15:ln-7. CPT1{alpha} over-expression increased mitochondrial long-chain fatty acid oxidation about 6-fold. Addition of palmitic acid (PA) decreased viability of CPT1{alpha} over-expressing cells in a concentration-dependent manner. Both, PA and CPT1{alpha} over-expression increased cell death. Interestingly,more » PA reduced total cell number only in cells over-expressing CPT1{alpha}, suggesting an effect on cell proliferation that requires PA translocation across the mitochondrial inner membrane. This inducible expression system should be well suited to study the roles of CPT1 and fatty acid oxidation in lipotoxicity and metabolism in vivo.« less

Biparental defensive endowment of eggs with acquired plant alkaloid in the moth Utetheisa ornatrix.

PubMed Central

Dussourd, D E; Ubik, K; Harvis, C; Resch, J; Meinwald, J; Eisner, T

1988-01-01

The eggs of Utetheisa ornatrix contain pyrrolizidine alkaloids. These compounds are contributed by both parents, who sequester them as larvae from their food plants. Females receive alkaloid from the males at mating, apparently by seminal infusion, and transmit this alkaloid together with alkaloid of their own to the eggs. Field and laboratory tests showed that the alkaloids protect eggs from predators. The alkaloidal contribution of the male, although smaller than that of the female, itself provides significant egg protection. A previously identified pheromone, derived by the male from the alkaloid and emitted during precopulatory behavior, may announce the male alkaloidal worth to the female. PMID:3413071

Alkaloids in bufonid toads (melanophryniscus): temporal and geographic determinants for two argentinian species.

PubMed

Daly, J W; Wilham, J M; Spande, T F; Garraffo, H M; Gil, R R; Silva, G L; Vaira, M

2007-04-01

Bufonid toads of the genus Melanophryniscus represent one of several lineages of anurans with the ability to sequester alkaloids from dietary arthropods for chemical defense. The alkaloid profile for Melanophryniscus stelzneri from a location in the province of Córdoba, Argentina, changed significantly over a 10-year period, probably indicating changes in availability of alkaloid-containing arthropods. A total of 29 alkaloids were identified in two collections of this population. Eight alkaloids were identified in M. stelzneri from another location in the province of Córdoba. The alkaloid profiles of Melanophryniscus rubriventris collected from four locations in the provinces of Salta and Jujuy, Argentina, contained 44 compounds and differed considerably between locations. Furthermore, alkaloid profiles of M. stelzneri and M. rubriventris strongly differed, probably reflecting differences in the ecosystem and hence in availability of alkaloid-containing arthropods.

Isolation, Identification, and Xanthine Oxidase Inhibition Activity of Alkaloid Compound from Peperomia pellucida

NASA Astrophysics Data System (ADS)

Fachriyah, E.; Ghifari, M. A.; Anam, K.

2018-04-01

The research of the isolation and xanthine oxidation inhibition activity of alkaloid compound from Peperomia pellucida has been carried out. Alkaloid extract is isolated by column chromatography and preparative TLC. Alkaloid isolate is identified spectroscopically by UV-Vis spectrophotometer, FT-IR, and LC-MS/MS. Xanthine oxidase inhibition activity is carried out by in vitro assay. The result showed that the alkaloid isolated probably has piperidine basic structure. The alkaloid isolate has N-H, C-H, C = C, C = O, C-N, C-O-C groups and the aromatic ring. The IC50 values of ethanol and alkaloid extract are 71.6658 ppm and 76.3318 ppm, respectively. Alkaloid extract of Peperomia pellucida showed higher activity than ethanol extract.

Gastric and duodenal antiulcer activity of alkaloids: a review.

PubMed

de Sousa Falcão, Heloina; Leite, Jacqueline Alves; Barbosa-Filho, José Maria; de Athayde-Filho, Petrônio Filgueiras; de Oliveira Chaves, Maria Célia; Moura, Marcelo Dantas; Ferreira, Anderson Luiz; de Almeida, Ana Beatriz Albino; Souza-Brito, Alba Regina Monteiro; de Fátima Formiga Melo Diniz, Margareth; Batista, Leônia Maria

2008-12-17

Peptic ulcer disease is a deep gastrointestinal erosion disorder that involves the entire mucosal thickness and can even penetrate the muscular mucosa. Numerous natural products have been evaluated as therapeutics for the treatment of a variety of diseases, including this one. These products usually derive from plant and animal sources that contain active constituents such as alkaloids, flavonoids, terpenoids, tannins and others. The alkaloids are natural nitrogen-containing secondary metabolites mostly derived from amino acids and found in about 20% of plants. There has been considerable pharmacological research into the antiulcer activity of these compounds. In this work we review the literature on alkaloids with antiulcer activity, which covers about sixty-one alkaloids, fifty-five of which have activity against this disease when induced in animals.

The serum concentrations of lupine alkaloids in orally-dosed Holstein cattle

USDA-ARS?s Scientific Manuscript database

Teratogenic alkaloid-containing Lupinus spp. cause significant losses to the cattle industry. Previous research has suggested that Holstein cattle clear toxic Delphinium alkaloids from their serum at a greater rate than beef cattle. The toxicokinetics of lupine alkaloids in Holsteins are not known...

Identification of the quinolizidine alkaloids in Sophora leachiana

USDA-ARS?s Scientific Manuscript database

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...

Low toxic and high soluble camptothecin derivative 2–47 effectively induces apoptosis of tumor cells in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Yao; Zhao, Hong-Ye; Jiang, Du

The cytotoxic activity of camptothecin derivatives is so high that these compounds need to be further modified before their successful application as anti-cancer agents clinically. In this study, we reported the synthesis and biological evaluation of a novel camptothecin derivative called compound 2–47. The changes in structure did not reduce its activity to inhibit DNA topoisomerase I. Compound 2–47 induced apoptosis of many tumor cells including leukemia cells K562, Jurkat, HL-60, breast cancer cell BT-549, colon cancer cell HT-29 and liver cancer cell HepG2 with a half maximal inhibitory concentration (IC{sub 50}) of 2- to 3-fold lower than HCPT asmore » a control. In particular, 2–47 inhibited the proliferation of Jurkat cells with an IC{sub 50} of as low as 40 nM. By making use of Jurkat cell as a model, following treatment of Jurkat cells, compound 2–47 activated caspase-3 and PARP, resulting in a decreased Bcl-2/Bax ratio. These data showed that compound 2–47 induces Jurkat cell death through the mitochondrial apoptotic pathway. In addition, compound 2–47 showed a decreased cytotoxic activity against normal cells and an improved solubility in low-polar solvent. For example, compound 2–47 solutes in CHCl{sub 3} 130-fold higher than HCPT. Taken together, our data demonstrated that camptothecin derivative 2–47 notably inhibits the tumor cell proliferation through mitochondrial-mediated apoptosis in vitro. - Highlights: • Compound 2–47 showed a wide inhibitory effect on the tested tumor cell lines with an IC{sub 50} of 3 times lower than that of HCPT in general. • Compound 2–47 inhibited the proliferation of the human leukemia cell Jurkat at an IC{sub 50} of as low as 40 nM. • As compared to HCPT, compound 2–47 showed much reduced cytotoxicity on normal human cells. • As compared to others, compound 2–47 showed a hundreds-fold higher solubility in non-polar organic solution.« less

Improving and sustaining delivery of CPT for PTSD in mental health systems: a cluster randomized trial.

PubMed

Wiltsey Stirman, Shannon; Finley, Erin P; Shields, Norman; Cook, Joan; Haine-Schlagel, Rachel; Burgess, James F; Dimeff, Linda; Koerner, Kelly; Suvak, Michael; Gutner, Cassidy A; Gagnon, David; Masina, Tasoula; Beristianos, Matthew; Mallard, Kera; Ramirez, Vanessa; Monson, Candice

2017-03-06

Large-scale implementation of evidence-based psychotherapies (EBPs) such as cognitive processing therapy (CPT) for posttraumatic stress disorder can have a tremendous impact on mental and physical health, healthcare utilization, and quality of life. While many mental health systems (MHS) have invested heavily in programs to implement EBPs, few eligible patients receive EBPs in routine care settings, and clinicians do not appear to deliver the full treatment protocol to many of their patients. Emerging evidence suggests that when CPT and other EBPs are delivered at low levels of fidelity, clinical outcomes are negatively impacted. Thus, identifying strategies to improve and sustain the delivery of CPT and other EBPs is critical. Existing literature has suggested two competing strategies to promote sustainability. One emphasizes fidelity to the treatment protocol through ongoing consultation and fidelity monitoring. The other focuses on improving the fit and effectiveness of these treatments through appropriate adaptations to the treatment or the clinical setting through a process of data-driven, continuous quality improvement. Neither has been evaluated in terms of impact on sustained implementation. To compare these approaches on the key sustainability outcomes and provide initial guidance on sustainability strategies, we propose a cluster randomized trial with mental health clinics (n = 32) in three diverse MHSs that have implemented CPT. Cohorts of clinicians and clinical managers will participate in 1 year of a fidelity oriented learning collaborative or 1 year of a continuous quality improvement-oriented learning collaborative. Patient-level PTSD symptom change, CPT fidelity and adaptation, penetration, and clinics' capacity to deliver EBP will be examined. Survey and interview data will also be collected to investigate multilevel influences on the success of the two learning collaborative strategies. This research will be conducted by a team of

New CPT codes: hospital, consultation, emergency and nursing facility services.

PubMed

Zuber, T J; Henley, D E

1992-03-01

New evaluation and management codes were created by the Current Procedural Terminology (CPT) Editorial Panel to ensure more accurate and consistent reporting of physician services. The new hospital inpatient codes describe three levels of service for both initial and subsequent care. Critical care services are reported according to the total time spent by a physician providing constant attention to a critically ill patient. Consultation codes are divided into four categories: office/outpatient, initial inpatient, follow-up inpatient and confirmatory. Emergency department services for both new and established patients are limited to five codes. In 1992, nursing facility services are described with either comprehensive-assessment codes or subsequent-care codes. Hospital discharge services may be reported in addition to the comprehensive nursing facility assessment. Since the 1992 CPT book will list only the new codes, and since all insurance carriers will not be using these codes in 1992, physicians are encouraged to keep their 1991 code books and contact their local insurance carriers to determine which codes will be used.

Antiviral activity of aconite alkaloids from Aconitum carmichaelii Debx.

PubMed

Xu, Weiming; Zhang, Min; Liu, Hongwu; Wei, Kun; He, Ming; Li, Xiangyang; Hu, Deyu; Yang, Song; Zheng, Yuguo

2017-12-22

Four diterpenoid alkaloids, namely, (a) hypaconitine, (b) songorine, (c) mesaconitine and (d) aconitine, were isolated from the ethanol root extract of Aconitum carmichaelii Debx. The antiviral activities of these alkaloids against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) were evaluated. Antiviral activity test in vivo showed that compounds a and c, which were C19-diterpenoid alkaloids, showed inactivation efficacy values of 82.4 and 85.6% against TMV at 500 μg/mL, respectively. By contrast, compound c presented inactivation activity of 52.1% against CMV at 500 μg/mL, which was almost equal to that of the commercial Ningnanmycin (87.1% inactivation activity against TMV and 53.8% inactivation activity against CMV). C19-Diterpenoid alkaloids displayed moderate to high antiviral activity against TMV and CMV at 500 μg/mL, dosage plays an important role in antiviral activities. This paper is the first report on the evolution of aconite diterpenoid alkaloids for antiviral activity against CMV.

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.

Leptopyrine, new alkaloid from Leptopyrum fumarioides L. (Ranunculaceae).

PubMed

Doncheva, Tsvetelina; Solongo, Amgalan; Kostova, Nadezhda; Gerelt-Od, Yadamsuren; Selenge, Dangaa; Philipov, Stefan

2015-01-01

A new type of isoquinoline alkaloid leptopyrine was isolated from the aerial parts of Leptopyrum fumarioides L. (Ranunculaceae) of Mongolian origin. The known alkaloids protopine and thalifoline were isolated for the first time from this the species. All structures were established by physical and spectral analyses.

Isolation and structure elucidation of a new indole alkaloid from Rauvolfia serpentina hairy root culture: the first naturally occurring alkaloid of the raumacline group.

PubMed

Sheludko, Yuri; Gerasimenko, Irina; Kolshorn, Heinz; Stöckigt, Joachim

2002-05-01

A new monoterpenoid indole alkaloid, 10-hydroxy- N(alpha)-demethyl-19,20-dehydroraumacline ( 1), was isolated as a mixture of E- and Z-isomers from hairy root culture of Rauvolfia serpentina Benth. ex Kurz (Apocynaceae) and the structure was determined by 1D and 2D NMR analyses. The new indole alkaloid represents the first naturally occurring alkaloid of the raumacline group and its putative biosynthetical pathway is discussed.

Formicine ants: An arthropod source for the pumiliotoxin alkaloids of dendrobatid poison frogs

PubMed Central

Saporito, Ralph A.; Garraffo, H. Martin; Donnelly, Maureen A.; Edwards, Adam L.; Longino, John T.; Daly, John W.

2004-01-01

A remarkable diversity of bioactive lipophilic alkaloids is present in the skin of poison frogs and toads worldwide. Originally discovered in neotropical dendrobatid frogs, these alkaloids are now known from mantellid frogs of Madagascar, certain myobatrachid frogs of Australia, and certain bufonid toads of South America. Presumably serving as a passive chemical defense, these alkaloids appear to be sequestered from a variety of alkaloid-containing arthropods. The pumiliotoxins represent a major, widespread, group of alkaloids that are found in virtually all anurans that are chemically defended by the presence of lipophilic alkaloids. Identifying an arthropod source for these alkaloids has been a considerable challenge for chemical ecologists. However, an extensive collection of neotropical forest arthropods has now revealed a putative arthropod source of the pumiliotoxins. Here we report on the presence of pumiliotoxins in formicine ants of the genera Brachymyrmex and Paratrechina, as well as the presence of these ants in the stomach contents of the microsympatric pumiliotoxin-containing dendrobatid frog, Dendrobates pumilio. These pumiliotoxins are major alkaloids in D. pumilio, and Brachymyrmex and Paratrechina ants now represent the only known dietary sources of these toxic alkaloids. These findings further support the significance of ant-specialization and alkaloid sequestration in the evolution of bright warning coloration in poison frogs and toads. PMID:15128938

[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.

Prospects for testing Lorentz and CPT symmetry with antiprotons.

PubMed

Vargas, Arnaldo J

2018-03-28

A brief overview of the prospects of testing Lorentz and CPT symmetry with antimatter experiments is presented. The models discussed are applicable to atomic spectroscopy experiments, Penning-trap experiments and gravitational tests. Comments about the sensitivity of the most recent antimatter experiments to the models reviewed here are included.This article is part of the Theo Murphy meeting issue 'Antiproton physics in the ELENA era'. © 2018 The Author(s).

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.

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

Microcalorimetry studies of the antimicrobial actions of Aconitum alkaloids*

PubMed Central

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

2015-01-01

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. PMID:26238544

[A Case of Advanced Gastric Cancer with Long-Term Survival after Chemotherapy with Combined S-1 and CPT-11].

PubMed

Hiratsuka, Miyuki; Ishibashi, Yuji; Suematsu, Yuki; Suda, Hiroshi; Takahashi, Miyuki; Saito, Hiroyuki; Omori, Keita; Morita, Akihiko; Wakabayashi, Kazuhiko; Ito, Yutaka

2015-11-01

Here, we report a 54-year-old man diagnosed with type 3 advanced gastric cancer who underwent a total gastrectomy and splenectomy plus D2 lymphadenectomy. The pathologic diagnosis was Stage Ⅳ (T3N0H0P0CY1M1). Sixteen courses of combined S-1/CPT-11 chemotherapy were completed, at which time the CPT-11 was discontinued because of malaise, and S-1 alone was continued for a year. The patient is well and has been recurrence-free for 7 years. Thus, he is considered a long- term survivor who was treated with combination S-1/CPT-11 chemotherapy.

Using time-dependent indirect CP asymmetries to measure T and CPT violation in B0-Bbar0 mixing

NASA Astrophysics Data System (ADS)

Karan, Anirban; Nayak, Abinash Kumar; Sinha, Rahul; London, David

2018-06-01

Quantum field theory, which is the basis for all of particle physics, requires that all processes respect CPT invariance. It is therefore of paramount importance to test the validity of CPT conservation. In this Letter, we show that the time-dependent, indirect CP asymmetries involving B decays to a CP eigenstate contain enough information to measure T and CPT violation in B0-Bbar0 mixing, in addition to the standard CP-violating weak phases. Entangled B0Bbar0 states are not required (so that this analysis can be carried out at LHCb, as well as at the B factories), penguin pollution need not be neglected, and the measurements can be made using Bd0 or Bs0 mesons.

A kinetic clutch governs uncoiling by type IB topoisomerases

NASA Astrophysics Data System (ADS)

Neuman, Keir

2013-03-01

Type IB topoisomerases (Top1B) are essential enzymes that relax excessive DNA supercoiling associated with replication and transcription and are important drug targets for cancer chemotherapy. The natural compound camptothecin (CPT) and the cancer chemotherapeutics derived from it, irinotecan and topotecan, are highly specific inhibitors of human nuclear Type IB topoisomerase (nTop1). We employed a magnetic-tweezers based single-molecule DNA supercoil relaxation assay to measure the torque dependence of human nuclear Top1 relaxation (nTop1) and inhibition by CPT. For comparison, we examined the human mitochondrial (Top1mt) topoisomerase and an N-terminal deletion mutant of nTop1 (Top68). Despite substantial sequence homology in their core domains, nTop1 and Top1mt exhibit dramatic differences in sensitivity to torque and CPT, with Top68 betraying intermediate characteristics. In particular, nTop1 displays nearly torque-independent religation probability, distinguishing it from other Top1B enzymes studied to date. Kinetic modeling reveals a hitherto unobserved torque-independent transition linking the DNA rotation and religation phases of the enzymatic cycle. The parameters of this transition determine the torque sensitivity of religation, and the efficiency of CPT binding. This ``kinetic clutch'' mechanism explains the molecular basis of CPT sensitivity and more generally provides a framework with which to interpret Top1B activity and inhibition.

Alkaloids from Mongolian species Hypecoum lactiflorum Kar. et Kir. Pazij.

PubMed

Philipov, Stefan; Istatkova, Ralitsa; Denkova, Pavletta; Dangaa, Selenge; Samdan, Javzan; Krosnova, Marieta; Munkh-Amgalan, Chogsom

2009-01-01

A new secoberbine alkaloid (-)-N-methylcorydalisol was isolated from the aerial parts of Hypecoum lactiflorum Kar. et Kir. Pazij. (Papaveraceae) of Mongolian origin and was characterised. The known alkaloids of protopine and protoberberine type protopine, allocryptopine, (-)-N-methylcanadine and (-)-N-methylstylopine were also isolated. (-)-N-methylstylopine is a new alkaloid for the genus, while (-)-N-methylcanadine is new for the species. All structures were established by physical and spectral analysis.

Evidence for an ergot alkaloid gene cluster in Claviceps purpurea.

PubMed

Tudzynski, P; Hölter, K; Correia, T; Arntz, C; Grammel, N; Keller, U

1999-02-01

A gene (cpd1) coding for the dimethylallyltryptophan synthase (DMATS) that catalyzes the first specific step in the biosynthesis of ergot alkaloids, was cloned from a strain of Claviceps purpurea that produces alkaloids in axenic culture. The derived gene product (CPD1) shows only 70% similarity to the corresponding gene previously isolated from Claviceps strain ATCC 26245, which is likely to be an isolate of C. fusiformis. Therefore, the related cpd1 most probably represents the first C. purpurea gene coding for an enzymatic step of the alkaloid biosynthetic pathway to be cloned. Analysis of the 3'-flanking region of cpd1 revealed a second, closely linked ergot alkaloid biosynthetic gene named cpps1, which codes for a 356-kDa polypeptide showing significant similarity to fungal modular peptide synthetases. The protein contains three amino acid-activating modules, and in the second module a sequence is found which matches that of an internal peptide (17 amino acids in length) obtained from a tryptic digest of lysergyl peptide synthetase 1 (LPS1) of C. purpurea, thus confirming that cpps1 encodes LPS1. LPS1 activates the three amino acids of the peptide portion of ergot peptide alkaloids during D-lysergyl peptide assembly. Chromosome walking revealed the presence of additional genes upstream of cpd1 which are probably also involved in ergot alkaloid biosynthesis: cpox1 probably codes for an FAD-dependent oxidoreductase (which could represent the chanoclavine cyclase), and a second putative oxidoreductase gene, cpox2, is closely linked to it in inverse orientation. RT-PCR experiments confirm that all four genes are expressed under conditions of peptide alkaloid biosynthesis. These results strongly suggest that at least some genes of ergot alkaloid biosynthesis in C. purpurea are clustered, opening the way for a detailed molecular genetic analysis of the pathway.

pH-sensitive nanocargo based on smart polymer functionalized graphene oxide for site-specific drug delivery.

PubMed

Kavitha, Thangavelu; Abdi, Syed Izhar Haider; Park, Soo-Young

2013-04-14

Graphene oxide (GO) was functionalized covalently with pH-sensitive poly(2-(diethylamino) ethyl methacrylate) (PDEA) by surface-initiated in situ atom transfer radical polymerization. The structure of the PDEA-grafted GO (GO-PDEA) were examined by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis and atomic force microscopy. The grafted PDEA endowed the GO sheets with good solubility and stability in physiological solutions. Simple physisorption by π-π stacking and hydrophobic interactions on GO-PDEA can be used to load camptothecin (CPT), a widely used water-insoluble cancer drug. The loaded CPT was released only at the lower (acidic) pH normally found in a tumor environment but not in basic and neutral pH. GO-PDEA did not show practical toxicity to N2a cancer cells but the GO-PDEA-CPT complex exhibited high potency in killing N2a cancer cells in vitro. These results suggest that the GO-PDEA nanocargo carrier might be a promising material for site-specific anticancer drug delivery and controlled release.

Neutral Porphyrin Derivative Exerts Anticancer Activity by Targeting Cellular Topoisomerase I (Top1) and Promotes Apoptotic Cell Death without Stabilizing Top1-DNA Cleavage Complexes

PubMed Central

2017-01-01

Camptothecin (CPT) selectively traps topoisomerase 1-DNA cleavable complexes (Top1cc) to promote anticancer activity. Here, we report the design and synthesis of a new class of neutral porphyrin derivative 5,10-bis(4-carboxyphenyl)-15, 20-bis(4-dimethylaminophenyl)porphyrin (compound 8) as a potent catalytic inhibitor of human Top1. In contrast to CPT, compound 8 reversibly binds with the free enzyme and inhibits the formation of Top1cc and promotes reversal of the preformed Top1cc with CPT. Compound 8 induced inhibition of Top1cc formation in live cells was substantiated by fluorescence recovery after photobleaching (FRAP) assays. We established that MCF7 cells treated with compound 8 trigger proteasome-mediated Top1 degradation, accumulate higher levels of reactive oxygen species (ROS), PARP1 cleavage, oxidative DNA fragmentation, and stimulate apoptotic cell death without stabilizing apoptotic Top1-DNA cleavage complexes. Finally, compound 8 shows anticancer activity by targeting cellular Top1 and preventing the enzyme from directly participating in the apoptotic process. PMID:29290109

Overexpression of tropinone reductases alters alkaloid composition in Atropa belladonna root cultures.

PubMed

Richter, Ute; Rothe, Grit; Fabian, Anne-Katrin; Rahfeld, Bettina; Dräger, Birgit

2005-02-01

The medicinally applied tropane alkaloids hyoscyamine and scopolamine are produced in Atropa belladonna L. and in a small number of other Solanaceae. Calystegines are nortropane alkaloids that derive from a branching point in the tropane alkaloid biosynthetic pathway. In A. belladonna root cultures, calystegine molar concentration is 2-fold higher than that of hyoscyamine and scopolamine. In this study, two tropinone reductases forming a branching point in the tropane alkaloid biosynthesis were overexpressed in A. belladonna. Root culture lines with strong overexpression of the transcripts contained more enzyme activity of the respective reductase and enhanced enzyme products, tropine or pseudotropine. High pseudotropine led to an increased accumulation of calystegines in the roots. Strong expression of the tropine-forming reductase was accompanied by 3-fold more hyoscyamine and 5-fold more scopolamine compared with control roots, and calystegine levels were decreased by 30-90% of control. In some of the transformed root cultures, an increase of total tropane alkaloids was observed. Thus, transformation with cDNA of tropinone reductases successfully altered the ratio of tropine-derived alkaloids versus pseudotropine-derived alkaloids.

Parasitic fungus Claviceps as a source for biotechnological production of ergot alkaloids.

PubMed

Hulvová, Helena; Galuszka, Petr; Frébortová, Jitka; Frébort, Ivo

2013-01-01

Ergot alkaloids produced by the fungus Claviceps parasitizing on cereals, include three major groups: clavine alkaloids, d-lysergic acid and its derivatives and ergopeptines. These alkaloids are important substances for the pharmatech industry, where they are used for production of anti-migraine drugs, uterotonics, prolactin inhibitors, anti-Parkinson agents, etc. Production of ergot alkaloids is based either on traditional field cultivation of ergot-infected rye or on submerged cultures of the fungus in industrial fermentation plants. In 2010, the total production of these alkaloids in the world was about 20,000 kg, of which field cultivation contributed about 50%. This review covers the recent advances in understanding of the genetics and regulation of biosynthesis of ergot alkaloids, focusing on possible applications of the new knowledge to improve the production yield. Copyright © 2012 Elsevier Inc. All rights reserved.

Ergot alkaloids produced by submerged cultures of Claviceps zizaniae.

PubMed

Kantorová, Michaela; Kolínská, Renata; Pazoutová, Sylvie; Honzátko, Ales; Havlícek, Vladimír; Flieger, Miroslav

2002-07-01

Two ergopeptine alkaloids, alpha-ergocryptine (1) and its C(8) epimer alpha-ergocryptinine, have been isolated from the mycelium and fermentation broth of submerged cultures of Claviceps zizaniae CCM 8240. The structure of 1 was determined by HPLC/positive ion APCI MS and NMR analysis. Alkaloid concentrations of 10 microg/mL in 14-day-old fermentation broth and 1 mg/g of dry mycelium mass were found. These results are of considerable biotechnological interest since these were the only detectable alkaloids produced. Toxicity of naturally occurring sclerotia of C. zizaniae cannot be excluded.

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.

Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts

PubMed Central

Krauze, Michal T.; Noble, Charles O.; Kawaguchi, Tomohiro; Drummond, Daryl; Kirpotin, Dmitri B.; Yamashita, Yoji; Kullberg, Erika; Forsayeth, John; Park, John W.; Bankiewicz, Krystof S.

2007-01-01

We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts. In this study, we have evaluated the combination of a newly developed nanoparticle/liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin. Both drugs were detectable in the CNS for more than 36 days after a single CED application. Tissue half-life was 16.7 days for nLs-CPT-11 and 10.9 days for Doxil. The combination of the two agents produced synergistic cytotoxicity in vitro. In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly. Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed. These findings have implications for further clinical applications of CED-based treatment of brain tumors. PMID:17652269

Oxidation of Hepatic Carnitine Palmitoyl Transferase-I (CPT-I) Impairs Fatty Acid Beta-Oxidation in Rats Fed a Methionine-Choline Deficient Diet

PubMed Central

Bellanti, Francesco; Priore, Paola; Rollo, Tiziana; Tamborra, Rosanna; Siculella, Luisa; Vendemiale, Gianluigi; Altomare, Emanuele; Gnoni, Gabriele V.

2011-01-01

There is growing evidence that mitochondrial dysfunction, and more specifically fatty acid β-oxidation impairment, is involved in the pathophysiology of non-alcoholic steatohepatitis (NASH). The goal of the present study was to achieve more understanding on the modification/s of carnitinepalmitoyltransferase-I (CPT-I), the rate-limiting enzyme of the mitochondrial fatty acid β-oxidation, during steatohepatitis. A high fat/methionine-choline deficient (MCD) diet, administered for 4 weeks, was used to induce NASH in rats. We demonstrated that CPT-Iactivity decreased, to the same extent, both in isolated liver mitochondria and in digitonin-permeabilized hepatocytes from MCD-diet fed rats. At the same time, the rate of total fatty acid oxidation to CO2 and ketone bodies, measured in isolated hepatocytes, was significantly lowered in treated animals when compared to controls. Finally, an increase in CPT-I mRNA abundance and protein content, together with a high level of CPT-I protein oxidation was observed in treated rats. A posttranslational modification of rat CPT-I during steatohepatitis has been here discussed. PMID:21909411

Microstructural Evolution of Inconel 625 and Inconel 686CPT Weld Metal for Clad Carbon Steel Linepipe Joints: A Comparator Study

NASA Astrophysics Data System (ADS)

Maltin, Charles A.; Galloway, Alexander M.; Mweemba, Martin

2014-07-01

Microstructural evolution of Inconel 625 and Inconel 686CPT filler metals, used for the fusion welding of clad carbon steel linepipe, has been investigated and compared. The effects of iron dilution from the linepipe parent material on the elemental segregation potential of the filler metal chemistry have been considered. The results obtained provide significant evidence to support the view that, in Inconel 686CPT weld metal, the segregation of tungsten is a function of the level of iron dilution from the parent material. The data presented indicate that the incoherent phase precipitated in the Inconel 686CPT weld metal has a morphology that is dependent on tungsten enrichment and, therefore, iron dilution. Furthermore, in the same weld metal, a continuous network of finer precipitates was observed. The Charpy impact toughness of each filler metal was evaluated, and the results highlighted the superior impact toughness of the Inconel 625 weld metal over that of Inconel 686CPT.

Quaternary isoquinoline alkaloids from Xylopia parviflora.

PubMed

Nishiyama, Yumi; Moriyasu, Masataka; Ichimaru, Momoyo; Iwasa, Kinuko; Kato, Atsushi; Mathenge, Simon G; Chalo Mutiso, Patrick B; Juma, Francis D

2004-04-01

From the quaternary alkaloidal fraction of the bark and the root of Xylopia parviflora (Annonaceae), four isoquinoline alkaloids, xylopinidine, dehydrocoreximine, N, N-dimethylanomurine and N-methylphoebine were isolated along with the known compounds, pycnarrhine, lotusine, 6,7-dimethoxy-2-methyl-isoquinolinium salt, 1,2-dehydroreticuline, (-)-phellodendrine, (+)-tembetarine, (-)-litcubine, (+)-magnoflorine, tetradehydroreticuline, (-)-oblongine, (+)-menisperine, (+)-N-methylcorydine, stepharanine, (+)-xanthoplanine, dehydrodiscretine, jatrorrhizine and palmatine. 3,4-Dihydro-6,7-dimethoxy-2-methyl-isoquinolinium and N-methylpurpuerine were isolated as natural products for the first time. Their structures were determined on the basis of spectroscopic evidence.

Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats.

PubMed

Takasuna, K; Hagiwara, T; Hirohashi, M; Kato, M; Nomura, M; Nagai, E; Yokoi, T; Kamataki, T

1998-01-01

SN-38, a metabolite of irinotecan hydrochloride (CPT-11), is considered to play a key role in the development of diarrhea as well as in the antitumor activity of CPT-11. We have previously found that the inhibition of beta-glucuronidase, which hydrolyzes detoxified SN-38 (SN-38 glucuronide) to reform SN-38, in the lumen by eliminating the intestinal microflora with antibiotics, markedly ameliorates the intestinal toxicity of CPT-11 in rats. In this study we compared the disposition of CPT-11 and its metabolites in rats treated with and without antibiotics. Rats were given drinking water containing 1 mg/ml penicillin and 2 mg/ml streptomycin from 5 days before the administration of CPT-11 (60 mg/kg i.v.) and throughout the experiment. CPT-11, SN-38 glucuronide and SN-38 concentrations in the blood, intestinal tissues and intestinal luminal contents were determined by HPLC. Antibiotics had little or no effect on the pharmacokinetics of CPT-11, SN-38 glucuronide or SN-38 in the blood, or in the tissues or contents of the small intestine, which has less beta-glucuronidase activity in its luminal contents. In contrast, antibiotics markedly reduced the AUC1-24 h of SN-38 (by about 85%) in the large intestine tissue without changing that of CPT-11, and this was accompanied by a complete inhibition of the deconjugation of SN-38 glucuronide in the luminal contents. These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by beta-glucuronidase in the intestinal microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the beta-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine.

Poor permeability and absorption affect the activity of four alkaloids from Coptis.

PubMed

Cui, Han-Ming; Zhang, Qiu-Yan; Wang, Jia-Long; Chen, Jian-Long; Zhang, Yu-Ling; Tong, Xiao-Lin

2015-11-01

Coptidis rhizoma (Coptis) and its alkaloids exert various pharmacological functions in cells and tissues; however, the oral absorption of these alkaloids requires further elucidation. The present study aimed to examine the mechanism underlying the poor absorption of alkaloids, including berberine (BER), coptisine (COP), palmatine (PAL) and jatrorrhizine (JAT). An ultra‑performance liquid chromatography (UPLC) method was validated for the determination of BER, COP, PAL and JAT in the above experimental medium. In addition, the apparent oil‑water partition coefficient (Po/w); apparent permeability coefficient (Papp), determined using a parallel artificial membrane permeability assay (PAMPA) plate; membrane retention coefficient (R %); and effect of P‑glycoprotein (P‑gp) inhibitor on the Papp of the four alkaloids were investigated. The intestinal absorption rate constant (Ka) and absorption percentage (A %) of the four alkaloids were also determined. The results of the present study demonstrated that the Po/w of the four alkaloids in 0.1 mol·l‑1 HCl medium was significantly higher (P<0.01), compared with those of the alkaloids in phosphate buffer (pH 7.4). The Papp of BER was 1.0‑1.2x10‑6 cm·s‑1, determined using a PAMPA plate, and the Papp of BER, COP, PAL and JAT decreased sequentially. The concentrations of the four alkaloids on the apical‑to‑basolateral (AP‑BL) surface and the basolateral‑to‑apical (BL‑AP) surface increased in a linear manner, with increasing concentrations between 10 and 100 µmol. In addition, the transportation of BER on the BL‑AP surface was significantly faster (P<0.01), compared with that on the AP‑BL surface and, following the addition of verpamil (a P‑gp inhibitor), the Papp (AP‑BL) of the four alkaloids increased, whereas the Papp (BL‑AP) was significantly decreased (P<0.01). The rat intestinal perfusion experiment demonstrated that the four alkaloids were poorly absorbed; however, the Ka of BER

Distribution of Aconitum alkaloids in autopsy cases of aconite poisoning.

PubMed

Niitsu, Hisae; Fujita, Yuji; Fujita, Sachiko; Kumagai, Reiko; Takamiya, Masataka; Aoki, Yasuhiro; Dewa, Koji

2013-04-10

Aconite is a well-known toxic-plant containing Aconitum alkaloids such as aconitines, benzoylaconines, and aconins. We describe here the distribution of Aconitum alkaloids detected by liquid chromatography-tandem mass spectrometry (LC/MS/MS) in three autopsy cases of suicide by aconite poisoning. Case 1: a male in his fifties had eaten aconite leaves. The concentrations of jesaconitine in cardiac blood, urine, and kidney were 12.1 ng/ml, 993.0 ng/ml, and 114.2 ng/g, respectively. Case 2: a female in her fifties had eaten aconite root. The aconite root in the stomach included a high level of mesaconitine. The concentrations of mesaconitine in cardiac blood, liver, and kidney were 69.1 ng/ml, 960.9 ng/g, and 776.9 ng/g, respectively. Case 3: a male in his sixties had drunk liquor in which aconite root had been soaked. The concentrations of mesaconitine and aconitine in cardiac blood were 259.5 and 228.5 ng/ml, respectively. The Aconitum alkaloid levels were very high in the liver. The absorption of ethanol and Aconitum alkaloids might have been increased because of his having undergone total gastrectomy. In all three cases, the Aconitum alkaloid levels were high in the liver and kidney and low in the heart and cerebrum. The level in the cerebrum was lower than that in blood. Data on the distribution of the Aconitum alkaloids in the body in cases of aconite poisoning is useful to elucidate various actions of aconite alkaloids. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Activity of alkaloids on peptic ulcer: what's new?

PubMed

do Nascimento, Raphaela Francelino; de Sales, Igor Rafael Praxedes; de Oliveira Formiga, Rodrigo; Barbosa-Filho, José Maria; Sobral, Marianna Vieira; Tavares, Josean Fechine; Diniz, Margareth de Fátima Formiga Melo; Batista, Leônia Maria

2015-01-08

Peptic ulcer is a common disease characterized by lesions that affect the mucosa of the esophagus, stomach and/or duodenum, and may extend into the muscular layer of the mucosa. Natural products have played an important role in the process of development and discovery of new drugs, due to their wide structural diversity and present, mostly specific and selective biological activities. Among natural products the alkaloids, biologically active secondary metabolites, that can be found in plants, animals or microorganisms stand out. The alkaloids are compounds consisting of a basic nitrogen atom that may or may not be part of a heterocyclic ring. This review will describe 15 alkaloids with antiulcer activity in animal models and in vitro studies.

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... SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION DIETARY SUPPLEMENTS THAT PRESENT A SIGNIFICANT OR UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing...

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... SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION DIETARY SUPPLEMENTS THAT PRESENT A SIGNIFICANT OR UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing...

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... SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION DIETARY SUPPLEMENTS THAT PRESENT A SIGNIFICANT OR UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing...

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... SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION DIETARY SUPPLEMENTS THAT PRESENT A SIGNIFICANT OR UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing...

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... SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION DIETARY SUPPLEMENTS THAT PRESENT A SIGNIFICANT OR UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing...

The alkaloids of Delphinium cashmirianum.

PubMed

Shamma, M; Chinnasamy, P; Miana, G A; Khan, A; Bashir, M; Salazar, M; Patil, P; Beal, J L

1979-01-01

Dephinium cashmirianum Royle (Ranunculaceae) has yielded the new base cashmiradelphine (12), together with the known alkaloids anthranoyllycoctonine (9), lycaconitine (15), avadharidine (17), lappaconitine (4), and N-deacetyllappaconitine (7). Pyridinium chlorochromate oxidation of lycoctonine furnished the new aldehyde lycoctonal (11). The arrhythmogenic and heart rate effects of several of these diterpenoidal alkaloids have been measured on the isolated guinea atria. Lappaconitine was arrhythmogenic at 10(-4)M concentrations. But in contrast to the reference drug aconitine, lappaconitine did not increase the heart rate. In anesthetized rabbits injected with lappaconitine, N-deacetyllappaconitine, and lappaconine up to 1 mg/kg, cardiac arrhythmia was quickly observed. Even up to 5 mg/kg, the other substances were non-arrhythmogenic.

Recent investigations of ergot alkaloids incorporated into plant and/or animal systems

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids produced by fungi have a basic chemical structure but different chemical moieties at substituent sites resulting in various forms of alkaloids that are distinguishable from one another. Since the ergoline ring structure found in ergot alkaloids is similar to that of biogenic amines (...

Molecular insights into microbial β-glucuronidase inhibition to abrogate CPT-11 toxicity.

PubMed

Roberts, Adam B; Wallace, Bret D; Venkatesh, Madhu Kumar; Mani, Sridhar; Redinbo, Matthew R

2013-08-01

Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial β-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial β-glucuronidase inhibitors that inhibit Escherichia coli β-glucuronidase in vitro with Ki values between 180 nM and 2 μM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli β-glucuronidase without inhibiting purified mammalian β-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli β-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, β-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11-induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial β-glucuronidase inhibition, which may improve human drug efficacy and toxicity.

Molecular Insights into Microbial β-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity

PubMed Central

Roberts, Adam B.; Wallace, Bret D.; Venkatesh, Madhu Kumar; Mani, Sridhar

2013-01-01

Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial β-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial β-glucuronidase inhibitors that inhibit Escherichia coli β-glucuronidase in vitro with Ki values between 180 nM and 2 μM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli β-glucuronidase without inhibiting purified mammalian β-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli β-glucuronidase demonstrates that it contacts and orders only a portion of the “bacterial loop” present in microbial, but not mammalian, β-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11–induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial β-glucuronidase inhibition, which may improve human drug efficacy and toxicity. PMID:23690068

New alkaloids of the sarpagine group from Rauvolfia serpentina hairy root culture.

PubMed

Sheludko, Yuri; Gerasimenko, Irina; Kolshorn, Heinz; Stöckigt, Joachim

2002-07-01

Three new monoterpenoid indole alkaloids, 19(S),20(R)-dihydroperaksine (1), 19(S),20(R)-dihydroperaksine-17-al (2), and 10-hydroxy-19(S),20(R)-dihydroperaksine (3), along with 16 known alkaloids 4-19 were isolated from hairy root culture of Rauvolfia serpentina, and their structures were elucidated by 1D and 2D NMR analyses. Taking into account the stereochemistry of the new alkaloids and results of preliminary enzymatical studies, the putative biosynthetical relationships between the novel alkaloids are discussed.

[Comparative study on alkaloids of tissue-culture seedling and wild plant of Dendrobium huoshanense ].

PubMed

Chen, Nai-dong; Gao, Feng; Lin, Xin; Jin, Hui

2014-06-01

To compare the composition and content of alkaloid of Dendrobium huoshanense tissue-culture seedling and wild plant. A comparative evaluation on the quality was carried out by HPLC and TLC methods including the composition and the content of alkaloids. Remarkable variation existed in the two kinds of Dendrobium huoshanense. For the tissue-culture plant, only two alkaloids were checked out by both HPLC and TLC while four alkaloids were observed in the wild plant. The alkaloid content of tissue-culture seedling and wild plant was(0. 29 ± 0. 11)%o and(0. 43 ± 0. 15) %o,respectively. Distinguished difference is observed in both composition and content of alkaloids from the annual shoots of different provenances of Dendrobium huoshanense. It suggested that the quality of tissue-culture seedling of Dendrobium huoshanense might be inconsistent with the wild plant. Furthermore, the established alkaloids-knock-out HPLC method would provide a new research tool on quality control of Chinese medicinal materials which contain unknown alkaloids.

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.

Identification, occurrence and activity of quinazoline alkaloids in Peganum harmala.

PubMed

Herraiz, Tomás; Guillén, Hugo; Arán, Vicente J; Salgado, Antonio

2017-05-01

Peganum harmala L. is a medicinal plant from the Mediterranean region and Asia currently used for recreative psychoactive purposes (Ayahuasca analogue), and increasingly involved in toxic cases. Its psychopharmacological and toxicological properties are attributed to quinazoline and β-carboline alkaloids. In this work three major quinazoline alkaloids were isolated from P. harmala extracts and characterized as peganine (vasicine), deoxypeganine (deoxyvasicine) and a novel compound identified by HPLC-DAD-MS and NMR as peganine β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (peganine glycoside). Peganine appeared in flowers and leaves in high levels; high amounts of deoxypeganine and peganine were found in immature and green fruits whereas peganine and peganine glycoside accumulated in high amount in dry seeds reaching up to 1 and 3.9% (w/w), respectively. Roots and stems contained low amount of quinazolines. Seeds extracts containing both quinazoline and β-carboline alkaloids potently inhibited human monoamine oxidase (MAO)-A. However, quinazoline alkaloids did not contribute to MAO inhibition that was due to β-carbolines, suggesting that MAO-related psychoactive or toxic actions do not arise from quinazolines. Quinazoline alkaloids were poor radical scavengers in the ABTS assay whereas seed extracts had good activity. Quinazoline alkaloids are known to exert bronchodilator and abortifacient actions, and could contribute to such effects reported in P. harmala. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pharmacological actions of Uncaria alkaloids, rhynchophylline and isorhynchophylline.

PubMed

Shi, Jing-Shan; Yu, Jun-Xian; Chen, Xiu-Ping; Xu, Rui-Xia

2003-02-01

The pharmacological actions of Uncaria alkaloids, rhynchophylline and isorhynchophylline extracted from Uncaria rhynchophylla Miq Jacks were reviewed. The alkaloids mainly act on cardiovascular system and central nervous system including the hypotension, brachycardia, antiarrhythmia, and protection of cerebral ischemia and sedation. The active mechanisms were related to blocking of calcium channel, opening of potassium channel, and regulating of nerve transmitters transport and metabolism, etc.

Aconite poisoning following the percutaneous absorption of Aconitum alkaloids.

PubMed

Chan, Thomas Y K

2012-11-30

In vitro experiment using the modified Franz-type diffusion cell has demonstrated that the human skin is permeable to aconitine and mesaconitine. To characterise the risk of systemic toxicity following the topical applications of aconite tincture and raw aconite roots, relevant reports of percutaneous absorption of Aconitum alkaloids and aconite poisoning are reviewed. Published reports indicate that aconite tincture and raw aconite roots can be absorbed through the skin into systemic circulation to cause fatal and non-fatal aconite poisoning. Both aconite tincture and raw aconite roots contain very high concentrations of Aconitum alkaloids, which allow penetration of the stratum corneum along the diffusion gradient. The risk of systemic toxicity is even higher if Aconitum alkaloids are held in occlusive contact with the skin and the epidermis (stratum corneum) is already damaged. The public should be warned of the danger in using these topical aconite preparations and the risk of systemic toxicity following percutaneous absorption of Aconitum alkaloids. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Effects of Neurofeekback Training on EEG, Continuous Performance Task (CPT), and ADHD Symptoms in ADHD-prone College Students.

PubMed

Ryoo, Manhee; Son, Chongnak

2015-12-01

This study explored the effects of neurofeedback training on Electroencephalogram (EEG), Continuous Performance Task (CPT) and ADHD symptoms in ADHD prone college students. Two hundred forty seven college students completed Korean Version of Conners' Adult ADHD Rating Scales (CAARS-K) and Korean Version of Beck Depression Inventory (K-BDI). The 16 participants who ranked in the top 25% of CAARS-K score and had 16 less of K-BDI score participated in this study. Among them, 8 participants who are fit for the research schedule were assigned to neurofeedback training group and 8 not fit for the research schedule to the control group. All participants completed Adult Attention Deficiency Questionnaire, CPT and EEG measurement at pretest. The neurofeedback group received 15 neurofeedback training sessions (5 weeks, 3 sessions per week). The control group did not receive any treatment. Four weeks after completion of the program, all participants completed CAARS-K, Adult Attention Deficiency Questionnaire, CPT and EEG measurement for post-test. The neurofeedback group showed more significant improvement in EEG, CPT performance and ADHD symptoms than the control group. The improvements were maintained at follow up. Neurofeedback training adjusted abnormal EEG and was effective in improving objective and subjective ADHD symptoms in ADHD prone college students.

Pro-toxic dehydropyrrolizidine alkaloids in the traditional Andean herbal medicine “asmachilca”

PubMed Central

Colegate, Steven M.; Boppré, Michael; Monzón, Julio; Betz, Joseph M.

2015-01-01

Ethnopharmacological relevance Asmachilca is a Peruvian medicinal herb preparation ostensibly derived from Eupatorium gayanum Wedd. = Aristeguietia gayana (Wedd.) R.M. King & H. Rob. (Asteraceae: Eupatorieae). Decoctions of the plant have a reported bronchodilation effect that is purported to be useful in the treatment of respiratory allergies, common cold and bronchial asthma. However, its attractiveness to pyrrolizidine alkaloid-pharmacophagous insects indicated a potential for toxicity for human consumers. Aim of the study To determine if commercial asmachilca samples, including fully processed herbal teas, contain potentially toxic 1,2-dehydropyrrolizidine alkaloids. Materials and methods Two brands of “Asmachilca” herbal tea bags and four other commercial samples of botanical materials for preparing asmachilca medicine were extracted and analyzed using HPLC-esi(+)MS and MS/MS for the characteristic retention times and mass spectra of known dehydropyrrolizidine alkaloids. Other suspected dehydropyrrolizidine alkaloids were tentatively identified based on MS/MS profiles and high resolution molecular weight determinations. Further structure elucidation of isolated alkaloids was based on 1D and 2D NMR spectroscopy. Results Asmachilca attracted many species of moths which are known to pharmacophagously gather dehydropyrrolizidine alkaloids. Analysis of 5 of the asmachilca samples revealed the major presence of the dehydropyrrolizidine alkaloid monoesters rinderine and supinine, and their N-oxides. The 6th sample was very similar but did not contain supinine or its N-oxide. Small quantities of other dehydropyrrolizidine alkaloid monoesters, including echinatine and intermedine, were also detected. In addition, two major metabolites, previously undescribed, were isolated and identified as dehydropyrrolizidine alkaloid monoesters with two “head-to-tail” linked viridifloric and/or trachelanthic acids. Estimates of total pyrrolizidine alkaloid and N

[Recent results on the pharmacodynamics of Strychnos malgaches alkaloids].

PubMed

Rasoanaivo, P; Ratsimamanga-Urverg, S; Frappier, F

1996-01-01

Investigation of Strychnos (Loganiaceae) shrubs and trees was initiated by their traditional uses of their inherent poisons on arrows: this led to the discovery of strychnine and curare alkaloids. Subsequently, phytochemical investigation of several Strychnos species has shown great structural diversity of the alkaloid constituent which also display various biological effects, i.e. convulsive and relaxant effects on muscles, and antimicrobial, antitumor and antihypertensive properties. Ethnobotanical field work conducted in different regions of Madagascar revealed that infusion of three Strychnos species, S. mostueoides, S. myrtoides and S. diplotricha, is used in association with subcurative doses of chloroquine to treat chronic malaria. Bioassayfractionation led to the isolation of two major bioactive components, strychnobrasiline and malagashanine. Whereas strychnobrasiline is a previously known chemical compound, malagashanine is the first in a series of a new subtype of Strychnos alkaloids. These two alkaloids are devoid of intrinsic antimalarial effects, both in vitro (IC50 = 73.0 micrograms/ml for strychnobrasiline and 69.1 micrograms/ml for malagashanine) and in vivo (10 mg/kg conferred a 5% suppression of parasitemia). When these alkaloids are combined with chloroquine at doses much lower than required for antiplasmodial effects, they greatly enhance the chloroquine action in a dose dependent manner as seen by the isobologram method. Several minor alkaloids structurally related to malagashanine were also isolated from Madagascan Strychnos. They all enhance, to greater or lesser degrees, the chloroquine effectiveness. Interestingly, there is a positive correlation between the ethnomedical use of the three Strychnos species as chloroquine adjuvants and the chloroquine-potentiating effects of malagashanine and strychnobrasiline isolated from them. After preliminary toxicological studies, infusion of stem barks of S. myrtoides in association with chloroquine

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.

Alkaloid production in Vernonia cinerea: Callus, cell suspension and root cultures.

PubMed

Maheshwari, Priti; Songara, Bharti; Kumar, Shailesh; Jain, Prachi; Srivastava, Kamini; Kumar, Anil

2007-08-01

Fast-growing callus, cell suspension and root cultures of Vernonia cinerea, a medicinal plant, were analyzed for the presence of alkaloids. Callus and root cultures were established from young leaf explants in Murashige and Skoog (MS) basal media supplemented with combinations of auxins and cytokinins, whereas cell suspension cultures were established from callus cultures. Maximum biomass of callus, cell suspension and root cultures were obtained in the medium supplemented with 1 mg/L alpha-naphthaleneacetic acid (NAA) and 5 mg/L benzylaminopurine (BA), 1.0 mg/L NAA and 0.1 mg/L BA and 1.5 mg/L NAA, respectively. The 5-week-old callus cultures resulted in maximum biomass and alkaloid contents (750 microg/g). Cell suspension growth and alkaloid contents were maximal in 20-day-old cultures and alkaloid contents were 1.15 mg/g. A 0.2-g sample of root tissue regenerated in semi-solid medium upon transfer to liquid MS medium containing 1.5 mg/L NAA regenerated a maximum increase in biomass of 6.3-fold over a period of 5 weeks. The highest root growth and alkaloid contents of 2 mg/g dry weight were obtained in 5-week-old cultures. Maximum alkaloid contents were obtained in root cultures in vitro compared to all others including the alkaloid content of in vivo obtained with aerial parts and roots (800 microg/g and 1.2 mg/g dry weight, respectively) of V. cinerea.

A new strain of Claviceps purpurea accumulating tetracyclic clavine alkaloids.

PubMed

Schumann, B; Erge, D; Maier, W; Gröger, D

1982-05-01

A new strain of Claviceps was isolated from a blokked mutant of Claviceps purpurea. This strain accumulates substantial amounts of clavine alkaloids (2 g/l). The alkaloid fraction is composed of chanoclavine-I ( approximately 10%) and a mixture of agroclavine/elymoclavine (90%). Most suitable for alkaloid production in submerged culture is an ammoncitrate/sucrose medium. The genealogy of the new strain, designated Pepty 695/ch-I is the following one: Pepty 695/S (ergotoxine producer) --> Pepty 695/ch (secoergoline producer) --> Pepty 695/ch-I (tetracyclic clavine producer).

Development of a Terpenoid Alkaloid-like Compound Library Based on the Humulene Skeleton.

PubMed

Kikuchi, Haruhisa; Nishimura, Takehiro; Kwon, Eunsang; Kawai, Junya; Oshima, Yoshiteru

2016-10-24

Many natural terpenoid alkaloid conjugates show biological activity because their structures contain both sp 3 -rich terpenoid scaffolds and nitrogen-containing alkaloid scaffolds. However, their biosynthesis utilizes a limited set of compounds as sources of the terpenoid moiety. The production of terpenoid alkaloids containing various types of terpenoid moiety may provide useful, chemically diverse compound libraries for drug discovery. Herein, we report the construction of a library of terpenoid alkaloid-like compounds based on Lewis-acid-catalyzed transannulation of humulene diepoxide and subsequent sequential olefin metathesis. Cheminformatic analysis quantitatively showed that the synthesized terpenoid alkaloid-like compound library has a high level of three-dimensional-shape diversity. Extensive pharmacological screening of the library has led to the identification of promising compounds for the development of antihypolipidemic drugs. Therefore, the synthesis of terpenoid alkaloid-like compound libraries based on humulene is well suited to drug discovery. Synthesis of terpenoid alkaloid-like compounds based on several natural terpenoids is an effective strategy for producing chemically diverse libraries. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genome mining of ascomycetous fungi reveals their genetic potential for ergot alkaloid production.

PubMed

Gerhards, Nina; Matuschek, Marco; Wallwey, Christiane; Li, Shu-Ming

2015-06-01

Ergot alkaloids are important as mycotoxins or as drugs. Naturally occurring ergot alkaloids as well as their semisynthetic derivatives have been used as pharmaceuticals in modern medicine for decades. We identified 196 putative ergot alkaloid biosynthetic genes belonging to at least 31 putative gene clusters in 31 fungal species by genome mining of the 360 available genome sequences of ascomycetous fungi with known proteins. Detailed analysis showed that these fungi belong to the families Aspergillaceae, Clavicipitaceae, Arthrodermataceae, Helotiaceae and Thermoascaceae. Within the identified families, only a small number of taxa are represented. Literature search revealed a large diversity of ergot alkaloid structures in different fungi of the phylum Ascomycota. However, ergot alkaloid accumulation was only observed in 15 of the sequenced species. Therefore, this study provides genetic basis for further study on ergot alkaloid production in the sequenced strains.

The Amaryllidaceae alkaloids: biosynthesis and methods for enzyme discovery

PubMed Central

Kilgore, Matthew B.; Kutchan, Toni M.

2015-01-01

Amaryllidaceae alkaloids are an example of the vast diversity of secondary metabolites with great therapeutic promise. The identification of novel compounds in this group with over 300 known structures continues to be an area of active study. The recent identification of norbelladine 4′-O-methyltransferase (N4OMT), an Amaryllidaceae alkaloid biosynthetic enzyme, and the assembly of transcriptomes for Narcissus sp. aff. pseudonarcissus and Lycoris aurea highlight the potential for discovery of Amaryllidaceae alkaloid biosynthetic genes with new technologies. Recent technical advances of interest include those in enzymology, next generation sequencing, genetic modification, nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS). PMID:27340382

Targeted Isolation of Monoterpene Indole Alkaloids from Palicourea sessilis.

PubMed

Klein-Júnior, Luiz C; Cretton, Sylvian; Allard, Pierre-Marie; Genta-Jouve, Grégory; Passos, Carolina S; Salton, Juliana; Bertelli, Pablo; Pupier, Marion; Jeannerat, Damien; Heyden, Yvan Vander; Gasper, André L; Wolfender, Jean-Luc; Christen, Philippe; Henriques, Amélia T

2017-11-22

Phytochemical investigation of the alkaloid extract of Palicourea sessilis by LC-HRMS/MS using molecular networking and an in silico MS/MS fragmentation approach suggested the presence of several new monoterpene indole alkaloids. These compounds were isolated by semipreparative HPLC, and their structures confirmed by means of HRMS, NMR, and ECD measurements as 4-N-methyllyaloside (3), 4-N-methyl-3,4-dehydrostrictosidine (4), 4β-hydroxyisodolichantoside (6), and 4α-hydroxyisodolichantoside (7), as well as the known alkaloids alline (1), N-methyltryptamine (2), isodolichantoside (5), and 5-oxodolichantoside (8). In addition, the acetylcholinesterase inhibitory activity of the compounds was evaluated up to 50 μM.

Endophyte-associated ergot alkaloids

USDA-ARS?s Scientific Manuscript database

Fescue toxicosis is a very costly (greater than $600 million/annually) for the cattle, horse and small ruminant industries. The tall fescue forage responsible for this intoxication is infected with an endophytic fungus (Neotyphodium coenophialum) that produces ergot alkaloids, which are toxic to th...

Organ-specific carboxylesterase profiling identifies the small intestine and kidney as major contributors of activation of the anticancer prodrug CPT-11

PubMed Central

Hatfield, M. Jason; Tsurkan, Lyudmila; Garrett, Michael; Shaver, Timothy M.; Hyatt, Janice L.; Edwards, Carol C.; Hicks, Latorya D.; Potter, Philip M.

2010-01-01

The activation of the anticancer prodrug CPT-11, to its active metabolite SN-38, is primarily mediated by carboxylesterases (CE). In humans, three CEs have been identified, of which human liver CE (hCE1; CES1) and human intestinal CE (hiCE; CES2) demonstrate significant ability to hydrolyze the drug. However, while the kinetic parameters of CPT-11 hydrolysis have been measured, the actual contribution of each enzyme to activate the drug in biological samples has not been addressed. Hence, we have used a combination of specific CE inhibition and conventional chromatographic techniques to determine the amounts, and hydrolytic activity, of CEs present within human liver, kidney, intestinal and lung specimens. These studies confirm that hiCE demonstrates the most efficient kinetic parameters for CPT-11 activation, however, due to the high levels of hCE1 that are expressed in liver, the latter enzyme can contribute up to 50% of the total of drug hydrolysis in this tissue. Conversely, in human duodenum, jejunum, ileum and kidney, where hCE1 expression is very low, greater than 99% of the conversion of CPT-11 to SN-38 was mediated by hiCE. Furthermore, analysis of lung microsomal extracts indicated that CPT-11 activation was more proficient in samples obtained from smokers. Overall, our studies demonstrate that hCE1 plays a significant role in CPT-11 hydrolysis even though it is up to 100-fold less efficient at drug activation than hiCE, and that drug activation in the intestine and kidney are likely major contributors to SN-38 production in vivo. PMID:20833148

Alkaloid profiles and acetylcholinesterase inhibitory activities of Fumaria species from Bulgaria.

PubMed

Vrancheva, Radka Z; Ivanov, Ivan G; Aneva, Ina Y; Dincheva, Ivayla N; Badjakov, Ilian K; Pavlov, Atanas I

2016-01-01

GC-MS analysis of alkaloid profiles of five Fumaria species, naturally grown in Bulgaria (F. officinalis, F. thuretii, F. kralikii, F. rostellata and F. schrammii) and analysis of acetylcholinesterase inhibitory activity of alkaloid extracts were performed. Fourteen isoquinoline alkaloids were identified, with the principle ones being protopine, cryptopine, sinactine, parfumine, fumariline, fumarophycine, and fumaritine. Protopine contents, defined by HPLC analysis varied between 210.6 ± 8.8 μg/g DW (F. schrammii) and 334.5 ± 7.1 μg/g DW. (F. rostellata). While all of the investigated alkaloid extracts significantly inhibited acetylcholinesterase activity, the F. kralikii demonstrated the highest level of inhibition (IC(50) 0.13 ± 0.01 mg extract/mL).

Ergot alkaloids in Norwegian wild grasses: a mass spectrometric approach.

PubMed

Uhlig, Silvio; Vikøren, Turid; Ivanova, Lada; Handeland, Kjell

2007-01-01

Ergot alkaloids are mycotoxins which are produced among fungi in the family Clavicipitaceae. Poisoning with ergot alkaloids is an important veterinary problem in animal husbandry and has recently also been recognised in wild animals. While the poisoning syndrome observed in domestic animals such as cattle, horses and sheep is usually caused by endophyte-infected grass, the recently observed ergotism among Norwegian cervids is probably due to infection of wild grasses with Claviceps. Mass spectrometry is today the method of choice for the rapid qualitative and quantitative determination of many natural compounds. This study uses tandem quadrupole mass spectrometry as well as ion trap mass spectrometry in connection with electrospray(+) ionisation for the quantification, screening and fragmentation of ergot alkaloids in extracts from Claviceps sclerotia that had been picked from wild grasses from several locations in Norway. Ergotamine, ergovaline, ergonovine and ergocryptine were available as standards and were quantified in the extracts, while ergocrystine, ergocornine, ergonine/ergosine, lysergic acid and lysergol were identified on the basis of their molecular weights and semi-quantified. Ergocrystine dominated the alkaloid spectrum of most extracts. Levels of the quantified alkaloids were in the range 0.2-9300 microg/g. Several unknown ergot alkaloids were found in the extracts. MS(n) experiments identified some as simple lysergic acid amide derivatives, while othes are probably related to ergocrystine and ergocryptine by dehydration, dehydrogenation and/or amino acid substitution at R(1) of the peptide moiety.

Actions of Piperidine Alkaloid Teratogens at Fetal Nicotinic Acetylcholine Receptors.

USDA-ARS?s Scientific Manuscript database

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...

Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors.

PubMed

Green, Benedict T; Lee, Stephen T; Panter, Kip E; Welch, Kevin D; Cook, Daniel; Pfister, James A; Kem, William R

2010-01-01

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 cleft palate. A pharmacodynamic comparison of the alkaloids ammodendrine, anabasine, anabaseine, anagyrine, and coniine in SH-SY5Y cells and TE-671 cells was made. These alkaloids and their enantiomers were more effective in depolarizing TE-671 cells which express the human fetal-muscle type nicotinic acetylcholine receptor (nAChR) relative to SH-SY5Y cells which predominately express autonomic nAChRs. The rank order of potency in TE-671 cells was: anabaseine>(+)-anabasine>(-)-anabasine > (+/-)-anabasine>anagyrine>(-)-coniine > (+/-)-coniine>(+)-coniine>(+/-)-ammodendrine>(+)-ammodendrine. The rank order potency in SH-SY5Y cells was: anabaseine>(+)-anabasine>(-)-coniine>(+)-coniine>(+)-ammodendrine>anagyrine>(-)-anabasine>(+/-)-coniine>(+/-)-anabasine>(-)-ammodendrine. The actions of these alkaloids at nAChRs in both cell lines could be distinguished by their maximum effects in depolarizing cell membrane potential. The teratogenic action of these compounds may be related to their ability to activate and subsequently desensitize nAChRs.

Claviceps nigricans and Claviceps grohii: their alkaloids and phylogenetic placement.

PubMed

Pazoutová, Sylvie; Olsovská, Jana; Sulc, Miroslav; Chudícková, Milada; Flieger, Miroslav

2008-06-01

Claviceps purpurea, C. grohii, C. zizaniae, C. cyperi, and C. nigricans are closely related ergot fungi and form a monophyletic clade inside the genus Claviceps. Analysis of alkaloid content in C. nigricans sclerotia using UPLC detected ergocristine (1), ergosine (2), alpha-ergocryptine (3), and ergocristam (4). Alkaloids 1, 3, and 4 were found in the sclerotia of C. grohii. The content of 4 in the mixture of alkaloids from C. nigricans and C. grohii (over 8% and over 20%, respectively) was unusually high. Submerged shaken cultures of C. nigricans produced no alkaloids, whereas C. grohii culture formed small amounts (15 mg L (-1)) of extracellular clavines and 1. In the previously used HPLC method the ergocristam degradation product could have been obscured by the ergosine peak. Therefore sclerotia of a C. purpurea habitat-specific population G2 with the dominant production of 1 and 2 have been reanalyzed, but no 4 was detected. The phylogeny of the C. purpurea-related species group is discussed with regard to alkaloid-specific nonribosomal peptide synthetase duplication leading to the production of two main ergopeptines instead of a single product.

Binary stress induces an increase in indole alkaloid biosynthesis in Catharanthus roseus

PubMed Central

Zhu, Wei; Yang, Bingxian; Komatsu, Setsuko; Lu, Xiaoping; Li, Ximin; Tian, Jingkui

2015-01-01

Catharanthus roseus is an important medicinal plant, which produces a variety of indole alkaloids of significant pharmaceutical relevance. In the present study, we aimed to investigate the potential stress-induced increase of indole alkaloid biosynthesis in C. roseus using proteomic technique. The contents of the detectable alkaloids ajmalicine, vindoline, catharanthine, and strictosidine in C. roseus were significantly increased under binary stress. Proteomic analysis revealed that the abundance of proteins related to tricarboxylic acid cycle and cell wall was largely increased; while, that of proteins related to tetrapyrrole synthesis and photosynthesis was decreased. Of note, 10-hydroxygeraniol oxidoreductase, which is involved in the biosynthesis of indole alkaloid was two-fold more abundant in treated group compared to the control. In addition, mRNA expression levels of genes involved in the indole alkaloid biosynthetic pathway indicated an up-regulation in their transcription in C. roseus under UV-B irradiation. These results suggest that binary stress might negatively affect the process of photosynthesis in C. roseus. In addition, the induction of alkaloid biosynthesis appears to be responsive to binary stress. PMID:26284098

Chemical defense: Bestowal of a nuptial alkaloidal garment by a male moth on its mate

PubMed Central

Conner, William E.; Boada, Ruth; Schroeder, Frank C.; González, Andrés; Meinwald, Jerrold; Eisner, Thomas

2000-01-01

Males of the moth Cosmosoma myrodora (Arctiidae) acquire pyrrolizidine alkaloid by feeding on the excrescent fluids of certain plants (for instance, Eupatorium capillifolium). They incorporate the alkaloid systemically and as a result are protected against spiders. The males have a pair of abdominal pouches, densely packed with fine cuticular filaments, which in alkaloid-fed males are alkaloid laden. The males discharge the filaments on the female in bursts during courtship, embellishing her with alkaloid as a result. The topical investiture protects the female against spiders. Alkaloid-free filaments, from alkaloid-deprived males, convey no such protection. The males also transmit alkaloid to the female by seminal infusion. The systemic alkaloid thus received, which itself may contribute to the female's defense against spiders, is bestowed in part by the female on the eggs. Although paternal contribution to egg defense had previously been demonstrated for several arctiid moths, protective nuptial festooning of a female by its mate, such as is practiced by C. myrodora, appears to be without parallel among insects. PMID:11114202

Quinolizidine alkaloids from the curare adjuvant Clathrotropis glaucophylla.

PubMed

Sagen, Anne Lise; Gertsch, Jürg; Becker, Rita; Heilmann, Jörg; Sticher, Otto

2002-12-01

The bark of Clathrotropis glaucophylla (Fabaceae) is used as admixture of curare arrow poison by the Yanomami; Amerindians in Venezuela. A new quinolizidine alkaloid (QA), (-)-13alpha-hydroxy-15alpha-(1-hydroxyethyl)-anagyrine [(-)-clathrotropine], was isolated from the alkaloid extract of C. glaucophylla bark, together with eleven known QAs: (-)-anagyrine, (-)-thermopsine, (-)-baptifoline, (-)-epibaptifoline, (-)-rhombifoline, (-)-tinctorine, (-)-cytisine, (-)-N-methylcytisine, (-)-lupanine, (-)-6alpha-hydroxylupanine and (+)-5,6-dehydrolupanine. The isolation and structure elucidation were performed with the aid of chromatographic (TLC, HPLC and CC) and spectroscopic (UV and 1D/2D NMR) methods, and mass spectrometry. To our knowledge, this is the first time quinolizidine alkaloids have been isolated from an arrow poison ingredient. It is also the first report on Clathrotropis species being used for preparation of arrow poison.

Exploring the effect of Vitamin E in Cancer Chemotherapy- A Biochemical and Biophysical Insight.

PubMed

Bhori, Mustansir; Singh, Kanchanlata; Marar, Thankamani; MuraliKrishna, C

2018-05-16

Many oncologists contend that patient undergoing chemotherapy must avoid antioxidant supplementation as it may interfere with the activity of the drug. In the present investigation, we have explored the influence of vitamin E, a well known antioxidant on Camptothecin (CPT), a potent anti-cancer drug induced cell apoptosis and death of cervical cancer cells. HeLa cells were treated with different concentrations of CPT in presence and absence of 100μm vitamin E. Treated cells were subjected to cytotoxicity studies, catalase assay, DNA fragmentation assay, clonogenic assay and flow cytometry based apoptosis detection. Also, Raman spectroscopy a label free technique which provides global information in conjunction with multivariate tools like PCA, PCLDA and FDA, was investigated to explore vitamin E supplementation induced alterations. Our data based on biochemical and biophysical experimental analysis reveals that CPT causes DNA damage along with protein and lipid alteration culminating in cell death. Importantly, Raman spectroscopic analysis could uniquely differentiate the cluster of control and vitamin E control from CPT and CPT+Vit E treated cells. We conclusively prove that presence of vitamin E at 100μM concentration shows promising antioxidant activity and displays no modulatory role on CPT induced effect, thereby causing no possible hindrance with the efficacy of the drug. Vitamin E may prove beneficial to alleviate chemotherapy associated side effects in patients during clinical settings which may open the doors further for subsequent exploration in in vivo pre clinical studies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Tall fescue seed extraction and partial purification of ergot alkaloids

USDA-ARS?s Scientific Manuscript database

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...

Caste specific alkaloid chemistry of Solenopsis maboya and S

Treesearch

J.A. Torres; V.E. Zottig; J.E. Co; T.H. Jones; R.R. Snelling

2001-01-01

Examination of the alkaloids of Solenopsis maboya Snelling and comparison with those previously found in S. Torresi Snelling, reveals a clear example of caste-specific alkaloid production in the queens and workers of each species. The queens of Solenopsis maboya contain a single piperidine while the workers produce a different piperidine along with two indolizidine...

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.

Manzamine alkaloids: isolation, cytotoxicity, antimalarial activity and SAR studies.

PubMed

Ashok, Penta; Ganguly, Swastika; Murugesan, Sankaranarayanan

2014-11-01

The infectious disease Malaria is caused by different species of the genus Plasmodium. Resistance to quinoline antimalarial drugs and decreased susceptibility to artemisinin-based combination therapy have increased the need for novel antimalarial agents. Historically, natural products have been used for the treatment of infectious diseases. Identification of natural products and their semi-synthetic derivatives with potent antimalarial activity is an important method for developing novel antimalarial agents. Manzamine alkaloids are a unique group of β-carboline alkaloids isolated from various species of marine sponge displaying potent antimalarial activity against drug-sensitive and -resistant strains of Plasmodium. In this review, we demonstrate antimalarial potency, cytotoxicity and antimalarial SAR of manzamine alkaloids. Copyright © 2014 Elsevier Ltd. All rights reserved.

Unravelling the architecture and dynamics of tropane alkaloid biosynthesis pathways using metabolite correlation networks.

PubMed

Nguyen, Thi-Kieu-Oanh; Jamali, Arash; Lanoue, Arnaud; Gontier, Eric; Dauwe, Rebecca

2015-08-01

The tropane alkaloid spectrum in Solanaceae is highly variable within and between species. Little is known about the topology and the coordination of the biosynthetic pathways leading to the variety of tropine and pseudotropine derived esters in the alkaloid spectrum, or about the metabolic dynamics induced by tropane alkaloid biosynthesis stimulating conditions. A good understanding of the metabolism, including all ramifications, is however necessary for the development of strategies to increase the abundance of pharmacologically interesting compounds such as hyoscyamine and scopolamine. The present study explores the tropane alkaloid metabolic pathways in an untargeted approach involving a correlation-based network analysis. Using GC-MS metabolite profiling, the variation and co-variation among tropane alkaloids and primary metabolites was monitored in 60 Datura innoxia Mill. individuals, of which half were exposed to tropane alkaloid biosynthesis stimulating conditions by co-culture with Agrobacterium rhizogenes. Considerable variation was evident in the relative proportions of the tropane alkaloids. Remodeling of the tropane alkaloid spectrum under co-culture with A. rhizogenes involved a specific and strong increase of hyoscyamine production and revealed that the accumulation of hyoscyamine, 3-tigloyloxy-6,7-epoxytropane, and 3-methylbutyryloxytropane was controlled independently of the majority of tropane alkaloids. Based on correlations between metabolites, we propose a biosynthetic origin of hygrine, the order of esterification of certain di-oxygenated tropanes, and that the rate of acetoxylation contributes to control of hyoscyamine production. Overall, this study shows that the biosynthesis of tropane alkaloids may be far more complex and finely controlled than previously expected. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

Effects of benzylisoquinoline alkaloids on the larvae of polyphagous Lepidoptera.

PubMed

Miller, James S; Feeny, Paul

1983-06-01

Six benzylisoquinoline alkaloids were fed to the larvae of three polyphagous Lepidoptera species: Hyphantria cunea, Spodoptera eridania, and Lymantria dispar. Exposure of last instar larvae to alkaloid-containing diets over a 24-h period resulted in reduced feeding rates and reduced growth efficiencies. Lymantria dispar larvae reared from eggs on alkaloid diets took longer to reach the fifth instar, attained lower larval weights, and showed reduced survivorship. The benzylisoquinolines tested were not equally effective as toxins or feeding inhibitors. Some produced dramatic effects while others produced no effects. The relative responses of the three caterpillar species to the six alkaloids were similar. Those benzylisoquinolines with a methylene-dioxyphenyl (1,3-benzodioxole) group were consistently the most toxic or repellent while laudanosine, a relatively simple benzylisoquinoline, was generally innocuous. Available host records indicate that benzylisoquinoline-containing plants are avoided by the larvae of these moth species.

Genotoxic effects of structurally related beta-carboline alkaloids.

PubMed

Picada, J N; da Silva, K V; Erdtmann, B; Henriques, A T; Henriques, J A

1997-10-06

beta-Carboline alkaloids, found in medicinal plants, tobacco smoke and well-cooked foods, have shown a variety of actions in biological systems related to their interaction with DNA. Therefore, these alkaloids can be considered potentially mutagenic. In this work, the genotoxic, mutagenic, and cytotoxic activities of three aromatic beta-carboline alkaloids (harman, harmine, and harmol) and two dihydro-beta-carboline alkaloids (harmaline and harmalol) were evaluated by means of the Salmonella/microsome assay (Salmonella typhimurium TA98, TA97, TA100, and TA102) and SOS chromotest (Escherichia coli PQ37) with and without metabolic activation. Moreover, harman and harmine were analyzed by the micronucleus assay in vivo. It was shown that genotoxicity was inhibited by the addition of S9 mix for aromatic beta-carbolines harman and harmol in TA97. However, harmine showed signs of mutagenicity only in the presence of S9 mix in TA98 and TA97 frameshift strains. In the SOS chromotest, only harman induced SOS functions in the absence of S9 mix. Dihydro-beta-carbolines were not genotoxic in any of the microorganisms used. The negative responses obtained in the micronucleus assay indicated that harman and harmine were not able to induce chromosomal mutations.

Occurrence of Ergot and Ergot Alkaloids in Western Canadian Wheat and Other Cereals.

PubMed

Tittlemier, Sheryl A; Drul, Dainna; Roscoe, Mike; McKendry, Twylla

2015-07-29

A new method was developed to analyze 10 ergot alkaloids in cereal grains. Analytes included both "ine" and "inine" type ergot alkaloids. Validation of the method showed it performed with good accuracy and precision and that minor enhancement due to matrix effects was present during LC-MS/MS analysis, but was mitigated by use of an internal standard. The method was used to survey durum and wheat harvested in 2011, a year in which ergot infection was particularly widespread in western Canada. A strong linear relationship between the concentration of ergot alkaloids and the presence of ergot sclerotia was observed. In addition, shipments of cereals from 2010-2012 were also monitored for ergot alkaloids. Concentrations of total ergot alkaloids in shipments were lower than observed in harvest samples, and averaged from 0.065 mg/kg in barley to 1.14 mg/kg in rye. In shipments, the concentration of ergot alkaloids was significantly lower in wheat of higher grades.

Indole alkaloids from leaves and twigs of Rauvolfia verticillata.

PubMed

Zhang, Bing-Jie; Peng, Lei; Wu, Zhi-Kun; Bao, Mei-Fen; Liu, Ya-Ping; Cheng, Gui-Guang; Luo, Xiao-Dong; Cai, Xiang-Hai

2013-01-01

Seven new indole alkaloids, rauverines A-G (1-7), and 19 known indole alkaloids were isolated from the leaves and twigs of Rauvolfia verticillata. All compounds showed no cytotoxicity against five human cancer cell lines, human myeloid leukemia (HL-60), hepatocellular carcinoma (SMMC-7721), lung cancer (A-549), breast cancer (MCF-7), and colon cancer (SW480) cells.

Rapid Screening of Ergot Alkaloids in Sclerotia by MALDI-TOF Mass Spectrometry.

PubMed

Sivagnanam, Kumaran; Komatsu, Emy; Patrick, Susan; Rampitsch, Christoph; Perreault, Hélène; Gräfenhan, Tom

2016-07-01

Ergot is a common disease of wheat and other cereal grains that is predominantly caused by Claviceps purpurea in the field, often affecting crop yield in addition to the environment. Infected grain can be contaminated with dark sclerotia, which contain fungal metabolites such as ergot alkaloids. The occurrence of ergot alkaloids in cereal grain is a major health concern for humans and livestock. Effective and rapid screening of these mycotoxins is crucial for producers, processors, and consumers of cereal-based food and feed grain. Established methods of ergot alkaloid screening based on LC-MS or GC-MS require laborious processes. A novel method using matrix-assisted laser desorption ionization (MALDI)-time-of-flight (TOF) MS was developed to identify four ergot alkaloids. Using dihydroxybenzoic acid as the matrix, ergosine, ergocornine, ergocryptine, and ergocristine were readily detected in individual sclerotia of C. purpurea. The accuracy of the identified ergot alkaloids was further confirmed by tandem MS analysis. MALDI-TOF MS is suitable for high-throughput screening of ergot alkaloids because it permits rapid and accurate identification, simple sample preparation, and no derivatization or chromatographic separation.

Measurement of antiphotooxidative properties of isoquinoline alkaloids using transient thermal lens spectroscopy

NASA Astrophysics Data System (ADS)

Hung, J.; Castillo, J.; Laboren, I.; Rodríguez, M.; Hassegawa, M.

2005-11-01

The antiphotooxidative properties of boldine and chloride berberine were studied by time-resolved thermal lensing technique. These compounds belong to isoquinoline alkaloids possessing interesting biological activity (e.g. antibacterial, antimalarial, antitumor). Antiphotooxidative properties of the alkaloids were studied by mechanism of energy transference between powerful oxidizing agents such as singlet oxygen. Singlet oxygen was produced by energy transfer from chlorophyll-sensitized photooxidation of oil by exposure of high light intensities like laser. The lifetimes of singlet oxygen in dimethylsulfoxide, methanol and water were determined to confirm the assignment of the singlet molecular oxygen O II (1Δ g) in the experiments. In order to understand the effect of the alkaloids on active oxygen species, we carried out in detail an analysis of the thermal lensing signal. It was shown that the alkaloids can act as quenchers of singlet oxygen. To demonstrate the ability of the alkaloids to act efficient singlet oxygen acceptors, we have measured the fluorescence spectra of the studied alkaloids in the presence and in the absence of singlet oxygen. The antiphotooxidative activity of boldine and chloride berberine can be explained by the ability to quench singlet oxygen.

Aporphine alkaloids from Guatteria spp. with leishmanicidal activity.

PubMed

Montenegro, Hector; Gutiérrez, Marcelino; Romero, Luz I; Ortega-Barría, Eduardo; Capson, Todd L; Rios, Luis Cubilla

2003-07-01

Fractionation of Guatteria amplifolia yielded the alkaloids xylopine (1), nornuciferine (4), lysicamine (6), and laudanosine (5). Fractionation of Guatteria dumetorum yielded the alkaloids cryptodorine (2) and nornantenine (3). Compounds 1-4 demonstrated significant activity against Leishmania mexicana and L. panamensis. Xylopine (1) was among the most active compounds (LD 50 = 3 microM) and showed a 37-fold higher toxicity towards L. mexicana than macrophages, the regular host cells of Leishmania spp.

Predicting the spatial distribution of soil profile in Adapazari/Turkey by artificial neural networks using CPT data

NASA Astrophysics Data System (ADS)

Arel, Ersin

2012-06-01

The infamous soils of Adapazari, Turkey, that failed extensively during the 46-s long magnitude 7.4 earthquake in 1999 have since been the subject of a research program. Boreholes, piezocone soundings and voluminous laboratory testing have enabled researchers to apply sophisticated methods to determine the soil profiles in the city using the existing database. This paper describes the use of the artificial neural network (ANN) model to predict the complex soil profiles of Adapazari, based on cone penetration test (CPT) results. More than 3236 field CPT readings have been collected from 117 soundings spread over an area of 26 km2. An attempt has been made to develop the ANN model using multilayer perceptrons trained with a feed-forward back-propagation algorithm. The results show that the ANN model is fairly accurate in predicting complex soil profiles. Soil identification using CPT test results has principally been based on the Robertson charts. Applying neural network systems using the chart offers a powerful and rapid route to reliable prediction of the soil profiles.

Structure-Activity Relationship of Benzophenanthridine Alkaloids from Zanthoxylum rhoifolium Having Antimicrobial Activity

PubMed Central

Tavares, Luciana de C.; Zanon, Graciane; Weber, Andréia D.; Neto, Alexandre T.; Mostardeiro, Clarice P.; Da Cruz, Ivana B. M.; Oliveira, Raul M.; Ilha, Vinicius; Dalcol, Ionara I.; Morel, Ademir F.

2014-01-01

Zanthoxylum rhoifolium (Rutaceae) is a plant alkaloid that grows in South America and has been used in Brazilian traditional medicine for the treatment of different health problems. The present study was designed to evaluate the antimicrobial activity of the steam bark crude methanol extract, fractions, and pure alkaloids of Z. rhoifolium. Its stem bark extracts exhibited a broad spectrum of antimicrobial activity, ranging from 12.5 to 100 µg/mL using bioautography method, and from 125 to 500 µg/mL in the microdilution bioassay. From the dichloromethane basic fraction, three furoquinoline alkaloids (1–3), and nine benzophenanthridine alkaloids (4–12) were isolated and the antimicrobial activity of the benzophenanthridine alkaloids is discussed in terms of structure-activity relationships. The alkaloid with the widest spectrum of activity was chelerythrine (10), followed by avicine (12) and dihydrochelerythrine (4). The minimal inhibitory concentrations of chelerythrine, of 1.50 µg/mL for all bacteria tested, and between 3.12 and 6.25 µg/mL for the yeast tested, show this compound to be a more powerful antimicrobial agent when compared with the other active alkaloids isolated from Z. rhoifolium. To verify the potential importance of the methylenedioxy group (ring A) of these alkaloids, chelerythrine was selected to represent the remainder of the benzophenanthridine alkaloids isolated in this work and was subjected to a demethylation reaction giving derivative 14. Compared to chelerythrine, the derivative (14) was less active against the tested bacteria and fungi. Kinetic measurements of the bacteriolytic activities of chelerythrine against the bacteria Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) were determined by optical density based on real time assay, suggesting that its mechanism of action is not bacteriolytic. The present study did not detect hemolytic effects of chelerythrine on erythrocytes and found a protective effect

Distinct sesquiterpene pyridine alkaloids from in Salvadoran and Peruvian Celastraceae species.

PubMed

Callies, Oliver; Núñez, Marvin J; Perestelo, Nayra R; Reyes, Carolina P; Torres-Romero, David; Jiménez, Ignacio A; Bazzocchi, Isabel L

2017-10-01

As part of a bioprospecting program aimed at the discovery of undescribed natural products from Salvadoran and Peruvian flora, the phytochemical investigations of four Celastraceae species, Celastrus vulcanicola, Maytenus segoviarum, Maytenus jeslkii, and Maytenus cuzcoina, were performed. The current study reports the isolation and structural characterization of five previously undescribed macrolide sesquiterpene pyridine alkaloids, named vulcanicoline-A, cuzcoinine, vulcanicoline-B, jelskiine, and vulcanicoline-C, along with sixteen known alkaloids. The structures of the alkaloids were established by spectrometric and extensive 1D and 2D NMR spectroscopic analysis, including COSY, HSQC, HMBC, and ROESY experiments. The absolute configurations of alkaloids were proposed based on optical rotation sign, and biogenetic considerations. This study represents the first phytochemical analysis of Maytenus segoviarum. Copyright © 2017 Elsevier Ltd. All rights reserved.

Terpenoid-Alkaloids: Their Biosynthetic Twist of Fate and Total Synthesis.

PubMed

Cherney, Emily C; Baran, Phil S

2011-04-01

Terpenes and alkaloids are ever-growing classes of natural products that provide new molecular structures which inspire chemists and possess a broad range of biological activity. Terpenoid-alkaloids originate from the same prenyl units that construct terpene skeletons. However, during biosynthesis, a nitrogen atom (or atoms) is introduced in the form of β-aminoethanol, ethylamine, or methylamine. Nitrogen incorporation can occur either before, during, or after the cyclase phase. The outcome of this unique biosynthesis is the formation of natural products containing unprecedented structures. These complex structural motifs expose current limitations in organic chemistry, thus providing opportunities for invention. This review focuses on total syntheses of terpenoid-alkaloids and unique issues presented by this class of natural products. More specifically, it examines how these syntheses relate to the way terpenoid-alkaloids are made in Nature. Developments in chemistry that have facilitated these syntheses are emphasized, as well as chemical technology needed to conquer those that evade synthesis.

Drug development against tuberculosis: Impact of alkaloids.

PubMed

Mishra, Shardendu K; Tripathi, Garima; Kishore, Navneet; Singh, Rakesh K; Singh, Archana; Tiwari, Vinod K

2017-09-08

Despite of the advances made in the treatment and management, tuberculosis (TB) still remains one of main public health problem. The contrary effects of first and second-line anti-tuberculosis drugs have generated extended research interest in natural products in the hope of devising new antitubercular leads. Interestingly, plethoras of natural products have been discovered to exhibit activity towards various resistant strains of M. tuberculosis. Extensive applications of alkaloids in the field of therapeutics is well-established and nowday's researches being pursued to develop new potent drugs from natural sources for tuberculosis. Alkaloids are categorized in quite a few groups according to their structures and isolation from both terrestrial and marine sources. These new drugs might be a watershed in the battle against tuberculosis. This review summarizes alkaloids, which were found active against Mycobacteria since last ten years with special attention on the study of structure-activity relationship (SAR) and mode of action with their impact in drug discovery and development against tuberculosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Cytotoxic and Anti-HIV Phenanthroindolizidine Alkaloids from Cryptocarya chinensis

PubMed Central

Wu, Tian-Shung; Su, Chung-Ren; Lee, Kuo-Hsiung

2013-01-01

Bioassay-guided fractionation of the cytotoxic ethanol extract of Cryptocarya chinensis has led to the isolation of 11 compounds, including two phenanthroindolizidine alkaloids [(−)-antofine (1) and dehydroantofine (2)], five pavine alkaloids (3–7), and four proaporphine alkaloids (8–11). The structures of the isolated compounds were determined by means of NMR spectroscopic methods, and supported by HRMS and optical rotation data. Compounds 1 and 2 showed cytotoxic activity against four cancer cell lines, L1210, P388, A549, and HCT-8, with 1 being the most potent against A549 and HCT-8 with EC50 values of 0.002 and 0.001 μg/mL, respectively. In addition, 2 is first reported to exhibit significant anti-HIV activity. PMID:22816292

Alkaloids in plants and root cultures of Atropa belladonna overexpressing putrescine N-methyltransferase.

PubMed

Rothe, Grit; Hachiya, Akira; Yamada, Yasuyuki; Hashimoto, Takashi; Dräger, Birgit

2003-09-01

Putrescine N-methyltransferase (PMT) is the first alkaloid-specific enzyme for nicotine and tropane alkaloid formation. The pmt gene from Nicotiana tabacum was fused to the CaMV 35S promoter and integrated into the Atropa belladonna genome. Transgenic plants and derived root cultures were analysed for gene expression and for levels of alkaloids and their precursors. Scopolamine, hyoscyamine, tropine, pseudotropine, tropinone, and calystegines were found unaltered or somewhat decreased in pmt-overexpressing lines compared to controls. When root cultures were treated with 5% sucrose, calystegine levels were elevated in control roots, but were not affected in pmt-overexpressing roots. 1 microM auxin reduced calystegine levels in control roots, while in pmt-overexpressing roots all alkaloids remained unaltered. Expression level of pmt alone is apparently not limiting for tropane alkaloid formation in A. belladonna.

Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide.

PubMed

Melo, Maria Luisa P; Brito, Gerly A C; Soares, Rudy C; Carvalho, Sarah B L M; Silva, Johan V; Soares, Pedro M G; Vale, Mariana L; Souza, Marcellus H L P; Cunha, Fernando Q; Ribeiro, Ronaldo A

2008-04-01

Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established. Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11. Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-alpha and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and KC ELISA. CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-alpha, IL-1beta and KC level and TNF-alpha immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-alpha, IL-1beta and KC and TNF-alpha immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-alpha tissue level and TNF-alpha immuno-staining, but did not reduce the severity of diarrhea. These results suggest an important role of TNF-alpha, IL-1beta and KC in the pathogenesis of intestinal mucositis induced by CPT-11.

Quantification of Aconitum alkaloids in aconite roots by a modified RP-HPLC method.

PubMed

Jiang, Zhi-Hong; Xie, Ying; Zhou, Hua; Wang, Jing-Rong; Liu, Zhong-Qiu; Wong, Yuen-Fan; Cai, Xiong; Xu, Hong-Xi; Liu, Liang

2005-01-01

The three Aconitum alkaloids, aconitine (1), mesaconitine (2) and hypaconitine (3), are pharmacologically active but also highly toxic. A standardised method is needed for assessing the levels of these alkaloids in aconite roots in order to ensure the safe use of these plant materials as medicinal herbs. By optimising extraction, separation and measurement conditions, a reliable, reproducible and accurate method for the quantitative determination of all three Aconitum alkaloids in unprocessed and processed aconite roots has been developed. This method should be appropriate for use in the quality control of Aconitum products. The three Aconitum alkaloids were separated by a modified HPLC method employing a C18 column gradient eluted with acetonitrile and ammonium bicarbonate buffer. Quantification of Aconitum alkaloids, detected at 240 nm, in different batches of samples showed that the content of 1, 2 and 3 varied significantly. In general, the alkaloid content of unprocessed roots was higher than that of processed roots. These variations were considered to be the result of differences in species, processing methods and places of origin of the samples.

Synergistic retention strategy of RGD active targeting and radiofrequency-enhanced permeability for intensified RF & chemotherapy synergistic tumor treatment.

PubMed

Zhang, Kun; Li, Pei; He, Yaping; Bo, Xiaowan; Li, Xiaolong; Li, Dandan; Chen, Hangrong; Xu, Huixiong

2016-08-01

Despite gaining increasing attention, chelation of multiple active targeting ligands greatly increase the formation probability of protein corona, disabling active targeting. To overcome it, a synergistic retention strategy of RGD-mediated active targeting and radiofrequency (RF) electromagnetic field-enhanced permeability has been proposed here. It is validated that such a special synergistic retention strategy can promote more poly lactic-co-glycolic acid (PLGA)-based capsules encapsulating camptothecin (CPT) and solid DL-menthol (DLM) to enter and retain in tumor in vitro and in vivo upon exposure to RF irradiation, receiving an above 8 fold enhancement in HeLa retention. Moreover, the PLGA-based capsules can respond RF field to trigger the entrapped DLM to generate solid-liquid-gas (SLG) tri-phase transformation for enhancing RF ablation and CPT release. Therefore, depending on the enhanced RF ablation and released CPT and the validated synergistic retention effect, the inhibitory outcome for tumor growth has gained an over 10-fold improvement, realizing RF ablation & chemotherapy synergistic treatment against HeLa solid tumor, which indicates a significant promise in clinical RF ablation. Copyright © 2016 Elsevier Ltd. All rights reserved.

The effect of 7, 8-methylenedioxylycoctonine-type diterpenoid alkaloids on the toxicity of tall larkspur (Delphinium spp.) in cattle.

PubMed

Welch, K D; Green, B T; Gardner, D R; Cook, D; Pfister, J A; Panter, K E

2012-07-01

Delphinium spp. contain numerous norditerpenoid alkaloids which are structurally delineated as 7, 8-methylenedioxylycoctonine (MDL) and N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type alkaloids. The toxicity of many tall larkspur species has been primarily attributed to their increased concentration of MSAL-type alkaloids, such as methyllycaconitine (MLA), which are typically 20 times more toxic than MDL-type alkaloids. However, the less toxic MDL-type alkaloids are often more abundant than MSAL-type alkaloids in most Delphinium barbeyi and Delphinium occidentale populations. Previous research demonstrated that MDL-type alkaloids increase the acute toxicity of MSAL-type alkaloids. In this study, we examined the role of MDL-type alkaloids on the overall toxicity of tall larkspur plants to cattle while controlling for the exact dose of MSAL-type alkaloids. Cattle were dosed with plant material from 2 different populations of tall larkspur containing either almost exclusively MDL- or MSAL-type alkaloids. These 2 plant populations were combined to create mixtures with ratios of 0.3:1, 1:1, 5:1, and 10:1 MDL- to MSAL-type alkaloids. The dose that elicited similar clinical signs of poisoning in mice and cattle was determined for each mixture on the basis of the MSAL-type alkaloid content. As the ratio of MDL- to MSAL-type alkaloids increased, the amount of MSAL-type alkaloids required to elicit clinical signs decreased. These results indicate that the less toxic MDL-type alkaloids in tall larkspur exacerbate the toxicity of the MSAL-type alkaloids. Consequently, both the amount of MSAL-type alkaloids and the amount of total alkaloids should be fully characterized to determine more accurately the relative toxicity of tall larkspur plant material.

Pyrrolizidine alkaloids from Heliotropium megalanthum.

PubMed

Reina, M; Gonzalez-Coloma, A; Gutierrez, C; Cabrera, R; Henriquez, J; Villarroel, L

1998-11-01

Two pyrrolizidine alkaloids, megalanthonine (1) and lycopsamine (2), have been isolated from Heliotropium megalanthum. The structure of the novel compound 1 was determined by spectroscopic methods. The insecticidal, antifeedant, and antifungal effects of compounds 1 and 2 have been evaluated.

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.

Effect of feeding fescue seed containing ergot alkaloid toxins on stallion spermatogenesis and sperm cells.

PubMed

Fayrer-Hosken, R; Stanley, A; Hill, N; Heusner, G; Christian, M; De La Fuente, R; Baumann, C; Jones, L

2012-12-01

The cellular effects of tall fescue grass-associated toxic ergot alkaloids on stallion sperm and colt testicular tissue were evaluated. This was a continuation of an initial experiment where the effects of toxic ergot alkaloids on the stallion spermiogram were investigated. The only spermiogram parameter in exposed stallions that was affected by the toxic ergot alkaloids was a decreased gel-free volume of the ejaculate. This study examined the effect of toxic ergot alkaloids on chilling and freezing of the stallion sperm cells. The effect of toxic ergot alkaloids on chilled extended sperm cells for 48 h at 5°C was to make the sperm cells less likely to undergo a calcium ionophore-induced acrosome reaction. The toxic ergot alkaloids had no effect on the freezability of sperm cells. However, if yearling colts were fed toxic ergot alkaloids, then the cytological analysis of meiotic chromosome synapsis revealed a significant increase in the proportion of pachytene spermatocytes showing unpaired sex chromosomes compared to control spermatocytes. There was little effect of ergot alkaloids on adult stallions, but there might be a significant effect on yearling colts. © 2012 Blackwell Verlag GmbH.

Effect of Feeding Fescue Seed Containing Ergot Alkaloid Toxins on Stallion Spermatogenesis and Sperm Cells

PubMed Central

Fayrer-Hosken, R; Stanley, A; Hill, N; Heusner, G; Christian, M; Fuente, R De La; Baumann, C; Jones, L

2012-01-01

Contents The cellular effects of tall fescue grass–associated toxic ergot alkaloids on stallion sperm and colt testicular tissue were evaluated. This was a continuation of an initial experiment where the effects of toxic ergot alkaloids on the stallion spermiogram were investigated. The only spermiogram parameter in exposed stallions that was affected by the toxic ergot alkaloids was a decreased gel-free volume of the ejaculate. This study examined the effect of toxic ergot alkaloids on chilling and freezing of the stallion sperm cells. The effect of toxic ergot alkaloids on chilled extended sperm cells for 48 h at 5 °C was to make the sperm cells less likely to undergo a calcium ionophore–induced acrosome reaction. The toxic ergot alkaloids had no effect on the freezability of sperm cells. However, if yearling colts were fed toxic ergot alkaloids, then the cytological analysis of meiotic chromosome synapsis revealed a significant increase in the proportion of pachytene spermatocytes showing unpaired sex chromosomes compared to control spermatocytes. There was little effect of ergot alkaloids on adult stallions, but there might be a significant effect on yearling colts. PMID:22524585

[Relativity among starch quantity, polysaccharides content and total alkaloid content of Dendrobium loddigesii].

PubMed

Zhu, Hua; Teng, Jianbei; Cai, Yi; Liang, Jie; Zhu, Yilin; Wei, Tao

2011-12-01

To find out the relativity among starch quantity, polysaccharides content and total alkaloid content of Dendrobium loddigesii. Microscopy-counting process was applied to starch quantity statistics, sulfuric acid-anthrone colorimetry was used to assay polysaccharides content and bromocresol green colorimetry was used to assay alkaloid content. Pearson product moment correlation analysis, Kendall's rank correlation analysis and Spearman's concordance coefficient analysis were applied to study their relativity. Extremely significant positive correlation was found between starch quantity and polysaccharides content, and significant negative correlation between alkaloid content and starch quantity was discovered, as well was between alkaloid content and polysaccharides content.

Bovine lateral saphenous veins exposed to ergopeptine alkaloids do not relax

USDA-ARS?s Scientific Manuscript database

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...

Pyrrole alkaloids from the fruits of Morus alba.

PubMed

Kim, Seon Beom; Chang, Bo Yoon; Hwang, Bang Yeon; Kim, Sung Yeon; Lee, Mi Kyeong

2014-12-15

Phytochemical investigation of the fruits of Morus alba afforded seventeen pyrrole alkaloids including five new compounds. The structures of five new pyrrole alkaloids, named morroles B-F (4, 5, 7, 16 and 17), were determined on the basis of spectroscopic interpretations. 4-[Formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl]butanoate (2) was synthesized by chemical reaction but first isolated from nature. Among isolated compounds, compounds 6 and 14 significantly inhibited pancreatic lipase activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Exploration of toxicity reducing mechanism of aconite alkaloids during decoction process using liquid chromatography-mass spectrometry].

PubMed

Chen, Ping; Chen, Yimin; Chen, Jia; Tong, Hongbin; Xu, Zhiliang

2013-11-01

A high performance liquid chromatography-electrospray ionization mass spectrometry method was developed for the determination of aconite alkaloids. It was used to investigate the degradation of alkaloids of Radix Aconiti Lateralis Preparata during decoction. Six alkaline degradation products were identified, and the degradation regularity of diester-diterpenoid alkaloids was confirmed during the test using standards. The dynamic changes of the amount of aconite alkaloids in the decoction of Radix Aconiti Lateralis Preparata were supervised. Along with the increase of decoction time, the concentrations of diester-diterpenoid alkaloids and lipo-alkaloid decreased significantly. The results can provide a scientific basis for the safety use of aconite.

Bovine lateral saphenous veins exposed to ergopeptine alkaloids do not relax

USDA-ARS?s Scientific Manuscript database

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 ...

Anthocyanin-rich blackberry extract suppresses the DNA-damaging properties of topoisomerase I and II poisons in colon carcinoma cells.

PubMed

Esselen, Melanie; Boettler, Ute; Teller, Nicole; Bachler, Simone; Hutter, Melanie; Rufer, Corinna E; Skrbek, Susanne; Marko, Doris

2011-07-13

In the present study, we addressed the question whether cyanidin-3-glucoside (C3G) or complex C3G-rich blackberry extracts affect human topoisomerases with special emphasis on the contribution of the potential degradation products phloroglucinol aldehyde (PGA) and protocatechuic acid (PCA). In HT29 colon carcinoma cells a C3G-rich blackberry extract suppressed camptothecin- (CPT-) or doxorubicin- (DOX-) induced stabilization of the covalent DNA-topoisomerase intermediate, thus antagonizing the effects of these classical topoisomerase poisons on DNA integrity. As a single compound, C3G (100 μM) decreased the DNA-damaging effects of CPT as well, but did not significantly affect those induced by DOX. At the highest applied concentration (100 μM), cyanidin protected DNA from CPT- and DOX-induced damage. Earlier reports on DNA-damaging properties of cyanidin were found to result most likely from the formation of hydrogen peroxide as an artifact in the cell culture medium when the incubation was performed in the absence of catalase. The suppression of hydrogen peroxide accumulation, achieved by the addition of catalase, demonstrated that cyanidin does not exhibit DNA-damaging properties in HT29 cells (up to 100 μM). The observed effects on topoisomerase interference and DNA protection against CPT or DOX were clearly limited to the parent compound and were not observed for the potential cyanidin degradation products PGA and PCA.

Acid-activatable oxidative stress-inducing polysaccharide nanoparticles for anticancer therapy.

PubMed

Yoo, Wooyoung; Yoo, Donghyuck; Hong, Eunmi; Jung, Eunkyeong; Go, Yebin; Singh, S V Berwin; Khang, Gilson; Lee, Dongwon

2018-01-10

Drug delivery systems have been extensively developed to enhance the therapeutic efficacy of drugs by altering their pharmacokinetics and biodistribution. However, the use of high quantities of drug delivery systems can cause toxicity due to their poor metabolism and elimination. In this study, we developed polysaccharide-based drug delivery systems which exert potent therapeutic effects and could display synergistic therapeutic effects with drug payloads, leading to dose reduction. Cinnamaldehyde, a major component of cinnamon is known to induce anticancer activity by generating ROS (reactive oxygen species). We developed cinnamaldehyde-conjugated maltodextrin (CMD) as a polymeric prodrug of cinnamaldehyde and a drug carrier. Cinnamaldehyde was conjugated to the hydroxyl groups of maltodextrin via acid-cleavable acetal linkages, allowing facile formulation of nanoparticles and drug encapsulation. CMD nanoparticles induced acid-triggered ROS generation to induce apoptotic cell death. Camptothecin (CPT) was used as a model drug to investigate the potential of CMD nanoparticles as a drug carrier and also evaluate the synergistic anticancer effects with CMD nanoparticles. CPT-loaded CMD nanoparticles exhibited significantly higher anticancer activity than empty CMD nanoparticles and CPT alone in the study of mouse xenograft models, demonstrating the synergistic therapeutic effects of CMD with CPT. Taken together, we believe that CMD nanoparticles hold tremendous potential as a polymeric prodrug of cinnamaldehyde and a drug carrier in anticancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Identification of a novel malonyl-CoA IC(50) for CPT-I: implications for predicting in vivo fatty acid oxidation rates.

PubMed

Smith, Brennan K; Perry, Christopher G R; Koves, Timothy R; Wright, David C; Smith, Jeffrey C; Neufer, P Darrell; Muoio, Deborah M; Holloway, Graham P

2012-11-15

Published values regarding the sensitivity (IC(50)) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted in vivo rates of fatty acid oxidation. Therefore we have re-examined M-CoA inhibition kinetics under various P-CoA (palmitoyl-CoA) concentrations in both isolated mitochondria and PMFs (permeabilized muscle fibres). PMFs have an 18-fold higher IC(50) (0.61 compared with 0.034 μM) in the presence of 25 μM P-CoA and a 13-fold higher IC(50) (6.3 compared with 0.49 μM) in the presence of 150 μM P-CoA compared with isolated mitochondria. M-CoA inhibition kinetics determined in PMFs predicts that CPT-I activity is inhibited by 33% in resting muscle compared with >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMFs appears to provide an M-CoA IC(50) that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate that the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the in vivo disconnect between M-CoA content and CPT-I flux within the context of exercise and Type 2 diabetes.

Binding of quinolizidine alkaloids to nicotinic and muscarinic acetylcholine receptors.

PubMed

Schmeller, T; Sauerwein, M; Sporer, F; Wink, M; Müller, W E

1994-09-01

Fourteen quinolizidine alkaloids, isolated from Lupinus albus, L. mutabilis, and Anagyris foetida, were analyzed for their affinity for nicotinic and/or muscarinic acetylcholine receptors. Of the compounds tested, the alpha-pyridones, N-methylcytisine and cytisine, showed the highest affinities at the nicotinic receptor, while several quinolizidine alkaloid types were especially active at the muscarinic receptor.

Modulation of Ergot Alkaloids in a Grass-Endophyte Symbiosis by Alteration of mRNA Concentrations of an Ergot Alkaloid Synthesis Gene.

PubMed

Mulinti, Prashanthi; Florea, Simona; Schardl, Christopher L; Panaccione, Daniel G

2016-06-22

The profile of ergot alkaloids in perennial ryegrass (Lolium perenne) containing the endophytic fungus Epichloë typhina × festucae includes high concentrations of the early pathway metabolites ergotryptamine and chanoclavine-I in addition to the pathway end-product ergovaline. Because these alkaloids differ in activity, we investigated strategies to alter their relative concentrations. An RNAi-based approach reduced the concentration of mRNA from the gene easA, which encodes an enzyme required for a ring closure that separates ergotryptamine and chanoclavine-I from ergovaline. Lower easA mRNA concentrations correlated with lower concentrations of ergovaline and higher concentrations of ergotryptamine and chanoclavine-I. Overexpression of easA led to higher concentrations of ergovaline in leaf blades but not in pseudostems; concentrations of the early pathway metabolites were not altered in overexpression strains. The data indicate that altering the concentration of mRNA from a single gene can change alkaloid flux, but the magnitude of the change was limited and variable.

Protein and alkaloid patterns of the floral nectar in some solanaceous species.

PubMed

Kerchner, András; Darók, Judit; Bacskay, Ivett; Felinger, Attila; Jakab, Gábor; Farkas, Ágnes

2015-09-01

The family Solanaceae includes several melliferous plants, which tend to produce copious amounts of nectar. Floral nectar is a chemically complex aqueous solution, dominated by sugars, but minor components such as amino acids, proteins, flavonoids and alkaloids are present as well. This study aimed at analysing the protein and alkaloid profile of the nectar in seven solanaceous species. Proteins were examined with SDS-PAGE and alkaloids were analyzed with HPLC. The investigation of protein profile revealed significant differences in nectar-protein patterns not only between different plant genera, but also between the three Nicotiana species investigated. SDS-PAGE suggested the presence of several Nectarin proteins with antimicrobial activity in Nicotiana species. The nectar of all tobacco species contained the alkaloid nicotine, N. tabacum having the highest nicotine content. The nectar of Brugmansia suaveolens, Datura stramonium, Hyoscyamus niger and Lycium barbarum contained scopolamine, the highest content of which was measured in B. suaveolens. The alkaloid concentrations in the nectars of most solanaceous species investigated can cause deterrence in honeybees, and the nectar of N. rustica and N. tabacum can be considered toxic for honeybees.

Effects of depletion of dihydropyrimidine dehydrogenase on focus formation and RPA phosphorylation.

PubMed

Someya, Masanori; Sakata, Koh-ichi; Matsumoto, Yoshihisa; Tauchi, Hiroshi; Kai, Masahiro; Hareyama, Masato; Fukushima, Masakazu

2012-01-01

Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase (DPYD), partially inhibits homologous recombination (HR) repair and has a radiosensitizing effect as well as enhanced sensitivity to Camptothecin (CPT). DPYD is the target protein for radiosensitization by Gimeracil. We investigated the mechanisms of sensitization of radiation and CPT by DPYD inhibition using DLD-1 cells treated with siRNA for DPYD. We investigated the focus formation of various kinds of proteins involved in HR and examined the phosphorylation of RPA by irradiation using Western blot analysis. DPYD depletion by siRNA significantly restrained the formation of radiation-induced foci of Rad51 and RPA, whereas it increased the number of foci of NBS1. The numbers of colocalization of NBS1 and RPA foci in DPYD-depleted cells after radiation were significantly smaller than in the control cells. These results suggest that DPYD depletion is attributable to decreased single-stranded DNA generated by the Mre11/Rad50/NBS1 complex-dependent resection of DNA double-strand break ends. The phosphorylation of RPA by irradiation was partially suppressed in DPYD-depleted cells, suggesting that DPYD depletion may partially inhibit DNA repair with HR by suppressing phosphorylation of RPA. DPYD depletion showed a radiosensitizing effect as well as enhanced sensitivity to CPT. The radiosensitizing effect of DPYD depletion plus CPT was the additive effect of DPYD depletion and CPT. DPYD depletion did not have a cell-killing effect, suggesting that DPYD depletion may not be so toxic. Considering these results, the combination of CPT and drugs that inhibit DPYD may prove useful for radiotherapy as a method of radiosensitization.

[Effects of Total Alkaloids of Harmaline on Learning and Memory in Vascular Dementia Rats].

PubMed

Zhang, Xiao-shuang; Sun, Jian-ning; Yu, Hui-ling

2015-11-01

To investigate the effects of total alkaloids of harmaline on learning and memory in vascular dementia rats, and its mechanism. The model rats of vascular dementia were established with bilateral carotid artery ligation. After 30 days, the model rats were randomly divided into six groups: sham group, model group, nicergoline tablets 7 mg/kg group, and 25, 12.5 and 6.25 mg/kg dose groups of total alkaloids of harmaline, the rats were given medicine for 30 days. Learning and memory abilities were tested by Morris water maze, histomorphology in hippocampal CA1 area were observed by HE staining, BAX and BCL-2 protein expression in hippocampal CA1 area were detected by immunohistochemistry. Compared with model group, 25 mg/kg group of total alkaloids of harmaline shortened the incubation period in the third and fourth day significantly, 12.5 mg/kg group of total alkaloids of harmaline shortened the incubation period in the fourth day. 25 and 12.5 mg/kg groups of total alkaloids of harmaline significantly increased the times crossing the target. Total alkaloids of harmaline improved the neurons pathological changes of rat in the hippocampus CA1 area, 25 and 12.5 mg/kg of total alkaloids of harmaline downregulated the expression of apoptosis proteins BAX, upregulated the protein expression of BCL-2. Total alkaloids of harmaline can improve the learning and memory abilities in vascular dementia rats, which probably is related to inhibiting apoptosis of hippocampus cell.

Unit-dose assay of tropine alkaloids and their synthetic analogs.

PubMed

Gomaa, C; Taha, A

1975-08-01

A charge-transfer spectrophotometric method was developed for unit-dose assay of the tropine alkaloids and some of their synthetic analogs. The high molar absorptivities of the charge-transfer bands of the alkaloids with iodine in ethylene dichloride resulted in improved recoveries and good precision, particularly at the low dose levels of pediatric and hypodermic tablets.

Clavine Alkaloids Gene Clusters of Penicillium and Related Fungi: Evolutionary Combination of Prenyltransferases, Monooxygenases and Dioxygenases

PubMed Central

Martín, Juan F.; Liras, Paloma

2017-01-01

The clavine alkaloids produced by the fungi of the Aspergillaceae and Arthrodermatacea families differ from the ergot alkaloids produced by Claviceps and Neotyphodium. The clavine alkaloids lack the extensive peptide chain modifications that occur in lysergic acid derived ergot alkaloids. Both clavine and ergot alkaloids arise from the condensation of tryptophan and dimethylallylpyrophosphate by the action of the dimethylallyltryptophan synthase. The first five steps of the biosynthetic pathway that convert tryptophan and dimethylallyl-pyrophosphate (DMA-PP) in chanoclavine-1-aldehyde are common to both clavine and ergot alkaloids. The biosynthesis of ergot alkaloids has been extensively studied and is not considered in this article. We focus this review on recent advances in the gene clusters for clavine alkaloids in the species of Penicillium, Aspergillus (Neosartorya), Arthroderma and Trychophyton and the enzymes encoded by them. The final products of the clavine alkaloids pathways derive from the tetracyclic ergoline ring, which is modified by late enzymes, including a reverse type prenyltransferase, P450 monooxygenases and acetyltransferases. In Aspergillus japonicus, a α-ketoglutarate and Fe2+-dependent dioxygenase is involved in the cyclization of a festuclavine-like unknown type intermediate into cycloclavine. Related dioxygenases occur in the biosynthetic gene clusters of ergot alkaloids in Claviceps purpurea and also in the clavine clusters in Penicillium species. The final products of the clavine alkaloid pathway in these fungi differ from each other depending on the late biosynthetic enzymes involved. An important difference between clavine and ergot alkaloid pathways is that clavine producers lack the enzyme CloA, a P450 monooxygenase, involved in one of the steps of the conversion of chanoclavine-1-aldehyde into lysergic acid. Bioinformatic analysis of the sequenced genomes of the Aspergillaceae and Arthrodermataceae fungi showed the presence of

Changes in plant defense chemistry (pyrrolizidine alkaloids) revealed through high-resolution spectroscopy

NASA Astrophysics Data System (ADS)

Carvalho, Sabrina; Macel, Mirka; Schlerf, Martin; Moghaddam, Fatemeh Eghbali; Mulder, Patrick P. J.; Skidmore, Andrew K.; van der Putten, Wim H.

2013-06-01

Plant toxic biochemicals play an important role in defense against natural enemies and often are toxic to humans and livestock. Hyperspectral reflectance is an established method for primary chemical detection and could be further used to determine plant toxicity in the field. In order to make a first step for pyrrolizidine alkaloids detection (toxic defense compound against mammals and many insects) we studied how such spectral data can estimate plant defense chemistry under controlled conditions. In a greenhouse, we grew three related plant species that defend against generalist herbivores through pyrrolizidine alkaloids: Jacobaea vulgaris, Jacobaea erucifolia and Senecio inaequidens, and analyzed the relation between spectral measurements and chemical concentrations using multivariate statistics. Nutrient addition enhanced tertiary-amine pyrrolizidine alkaloids contents of J. vulgaris and J. erucifolia and decreased N-oxide contents in S. inaequidens and J. vulgaris. Pyrrolizidine alkaloids could be predicted with a moderate accuracy. Pyrrolizidine alkaloid forms tertiary-amines and epoxides were predicted with 63% and 56% of the variation explained, respectively. The most relevant spectral regions selected for prediction were associated with electron transitions and Csbnd H, Osbnd H, and Nsbnd H bonds in the 1530 and 2100 nm regions. Given the relatively low concentration in pyrrolizidine alkaloids concentration (in the order of mg g-1) and resultant predictions, it is promising that pyrrolizidine alkaloids interact with incident light. Further studies should be considered to determine if such a non-destructive method may predict changes in PA concentration in relation to plant natural enemies. Spectroscopy may be used to study plant defenses in intact plant tissues, and may provide managers of toxic plants, food industry and multitrophic-interaction researchers with faster and larger monitoring possibilities.

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

Hexacyclic monoterpenoid indole alkaloids from Rauvolfia verticillata.

PubMed

Gao, Yuan; Yu, Ai-Lin; Li, Gen-Tao; Hai, Ping; Li, Yan; Liu, Ji-Kai; Wang, Fei

2015-12-01

Five new hexacyclic monoterpenoid indole alkaloids, rauvovertine A (1), 17-epi-rauvovertine A (2), rauvovertine B (3), 17-epi-rauvovertine B (4), and rauvovertine C (5) together with 17 known analogues were isolated from the stems of Rauvolfia verticillata. Compounds 1/2 and 3/4 were obtained as C-17 epimeric mixtures due to rapid hemiacetal tautomerism in solution. The structures of 1-5 were established by spectroscopic analysis and with the aid of molecular modeling. The new alkaloids were evaluated for their cytotoxicity in vitro against human tumor HL-60, SMMC-7721, A-549, MCF-7, and SW-480 cell lines. Copyright © 2015 Elsevier B.V. All rights reserved.

Analysis of Alkaloids from Physalis peruviana by Capillary GC, Capillary GC-MS, and GC-FTIR.

PubMed

Kubwabo, C; Rollmann, B; Tilquin, B

1993-04-01

The alkaloid composition of the aerial parts and roots of PHYSALIS PERUVIANA was analysed by capillary GC (GC (2)), GC (2)-MS and GC (2)-FTIR. Eight alkaloids were identified, three of those alkaloids are 3beta-acetoxytropane and two N-methylpyrrolidinylhygrine isomers, which were not previously found in the genus PHYSALIS. A reproduction of the identification of alkaloids detected in the plant by the use of retention indices has been proposed.

How polyamine synthesis inhibitors and cinnamic acid affect tropane alkaloid production.

PubMed

Marconi, Patricia L; Alvarez, María A; Pitta-Alvarez, Sandra I

2007-01-01

Hairy roots of Brugmansia candida produce the tropane alkaloids scopolamine and hyoscyamine. In an attempt to divert the carbon flux from competing pathways and thus enhance productivity, the polyamine biosynthesis inhibitors cyclohexylamine (CHA) and methylglyoxal-bis-guanylhydrazone (MGBG) and the phenylalanine-ammonia-lyase inhibitor cinnamic acid were used. CHA decreased the specific productivity of both alkaloids but increased significantly the release of scopolamine (approx 500%) when it was added in the mid-exponential phase. However, when CHA was added for only 48 h during the exponential phase, the specific productivity of both alkaloids increased (approx 200%), favoring scopolamine. Treatment with MGBG was detrimental to growth but promoted release into the medium of both alkaloids. However, when it was added for 48 h during the exponential phase, MGBG increased the specific productivity (approx 200%) and release (250- 1800%) of both alkaloids. Cinnamic acid alone also favored release but not specific productivity. When a combination of CHA or MGBG with cinnamic acid was used, the results obtained were approximately the same as with each polyamine biosynthesis inhibitor alone, although to a lesser extent. Regarding root morphology, CHA inhibited growth of primary roots and ramification. However, it had a positive effect on elongation of lateral roots.

Tests of CPT, Lorentz invariance and the WEP with antihydrogen

DOE Office of Scientific and Technical Information (OSTI.GOV)

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.

Relationships among Ergot Alkaloids, Cytochrome P450 Activity, and Beef Steer Growth

NASA Astrophysics Data System (ADS)

Rosenkrans, Charles; Ezell, Nicholas

2015-03-01

Determining a grazing animal’s susceptibility to ergot alkaloids has been a research topic for decades. Our objective was to determine if the Promega™ P450-Glo assay could be used to indirectly detect ergot alkaloids or their metabolites in urine of steers. The first experiment validated the effects of ergot alkaloids [0, 20, and 40 μM of ergotamine (ET), dihydroergotamine (DHET), and ergonovine (EN)] on human CYP3A4 using the P450-Glo assay (Promega™ V9800). With this assay, luminescence is directly proportional to CYP450 activity. Relative inhibition of in vitro cytochrome P450 activity was affected (P < 0.001) by an interaction between alkaloids and concentration. That interaction resulted in no concentration effect of EN, but within ET and DHET 20 and 40 µM concentrations inhibited CYP450 activity when compared with controls. In experiment 2, urine was collected from Angus-sired crossbred steers (n = 39; 216 ± 2.6 d of age; 203 ± 1.7 kg) after grazing tall fescue pastures for 105 d. Non-diluted urine was added to the Promega™ P450-Glo assay, and observed inhibition (3.7 % ± 2.7 of control). Urine content of total ergot alkaloids (331.1 ng/mg of creatinine ± 325.7) was determined using enzyme linked immunosorbent assay. Urine inhibition of CYP450 activity and total alkaloids were correlated (r = -0.31; P < 0.05). Steers were genotyped at CYP450 single nucleotide polymorphism, C994G. Steer genotype affected (P < 0.03) inhibition of CYP450 activity by urine; heterozygous steers had the least amount of CYP450 inhibition suggesting that genotyping cattle may be a method of identifying animals that are susceptible to ergot alkaloids. Although, additional research is needed, we demonstrate that the Promega™ P450-Glo assay is sensitive to ergot alkaloids and urine from steers grazing tall fescue. With some refinement the P450-Glo assay has potential as a tool for screening cattle for their exposure to fescue toxins.

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

Ornithine decarboxylase, polyamines, and pyrrolizidine alkaloids in senecio and crotalaria.

PubMed

Birecka, H; Birecki, M; Cohen, E J; Bitonti, A J; McCann, P 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.

Indole alkaloids and other constituents of Rauwolfia serpentina.

PubMed

Itoh, Atsuko; Kumashiro, Tomoko; Yamaguchi, Machiko; Nagakura, Naotaka; Mizushina, Yoshiyuki; Nishi, Toyoyuki; Tanahashi, Takao

2005-06-01

From the dried roots of Rauwolfia serpentina were isolated five new indole alkaloids, N(b)-methylajmaline (1), N(b)-methylisoajmaline (2), 3-hydroxysarpagine (3), yohimbinic acid (4), isorauhimbinic acid (5), a new iridoid glucoside, 7-epiloganin (6), and a new sucrose derivative, 6'-O-(3,4,5-trimethoxybenzoyl)glomeratose A (7), together with 20 known compounds. The structures of the new compounds were determined by spectroscopic and chemical means. The inhibitory activities of the selected alkaloids on topoisomerase I and II and their cytotoxicity against the human promyelocytic leukemia (HL-60) cell lines were assessed.

[Study on the extraction of the total alkaloids from Caulopyhllum robustum].

PubMed

Li, Yi-ping; Yang, Guang-de; He, Lang-chong

2007-02-01

To study the technological parameters of the extraction process of the total alkaloids from Caulopyhllum robstum. Taspine, whiVh is main component of the total alkaloids from Caulopyhllum robustum, was selected as an evaluating marker and determined by HPLC. The orthogonal test was used to optimize extracting conditions in the process of acid water extraction. Then the optimized conditions for purification using cation exchange resin were investigated. The optimized conditions in the process of acid water extraction were 1% hydrochloric acid as much as seven times of the medicine amount for 24hs and three times. Then the extraction of acid water was purified with a column of macroporous cation exchange resin LSD001 at 2 ml/min of flow rate, then eluted with 10BV of 4% aqueous ammonia ethanol. The extraction ratio of the total alkaloids was 1. 35% and the content of taspine of the total alkaloids was 6. 80%. This technology is simply, cheap effective and feasible for manufacture in great scale.

Development of Transcriptomic Resources for Interrogating the Biosynthesis of Monoterpene Indole Alkaloids in Medicinal Plant Species

PubMed Central

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

The effect of body condition on disposition of alkaloids from silvery lupine (Lupinus argenteus pursh) in sheep.

PubMed

Lopez-Ortiz, S; Panter, K E; Pfister, J A; Launchbaugh, K L

2004-09-01

Several species of lupine (Lupinus spp.) are poisonous to livestock, producing death in sheep and "crooked calf disease" in cattle. Range livestock cope with poisonous plants through learned foraging strategies or mechanisms affecting toxicant disposition. When a toxic plant is eaten, toxicant clearance may be influenced by the animal's nutritional and/or physiological status. This research was conducted to determine whether differences in body condition or short-term nutritional supplementation of sheep altered the disposition of lupine alkaloids given as a single oral dose of ground silvery lupine (Lupinus argenteus) seed. Ewes in average body condition (ABC, n = 9) and low body condition (LBC, n = 10) received a single dose of ground lupine seeds including pods (8.5 g/kg BW) via gavage on the first day of the experiment, and were then randomly assigned to one of two nutritional supplement treatments. Blood samples were taken 0 to 60 h after dosing to compare blood alkaloid concentration and to evaluate alkaloid absorption and elimination profiles. Concentrations of total alkaloid and anagyrine, 5,6 dehydrolupanine, lupanine, and alkaloid E were measured in serum. These four alkaloids constituted 78 and 75% of the total alkaloid concentration in serum for LBC vs. ABC groups, respectively. Initial analysis indicated that short-term supplementation had no effect on alkaloid disposition, and supplementation was removed from the statistical model. The highest concentration of total alkaloids was observed 2 h after dosing. Overall, serum total alkaloid and anagyrine levels (area under the curve) were higher (P < 0.01) for sheep in the LBC group. Serum peak concentrations of total alkaloid and anagyrine were higher in LBC vs. ABC groups (P < 0.05). Serum elimination of anagyrine, unknown alkaloid E, and lupanine was decreased in LBC vs. ABC treatments (P < 0.05). These results demonstrate that body condition is important in the disposition of lupine alkaloids; however

Off-target effect of the Epac agonist 8-pCPT-2'-O-Me-cAMP on P2Y12 receptors in blood platelets.

PubMed

Herfindal, Lars; Nygaard, Gyrid; Kopperud, Reidun; Krakstad, Camilla; Døskeland, Stein Ove; Selheim, Frode

2013-08-09

The primary target of the cAMP analogue 8-pCPT-2'-O-Me-cAMP is exchange protein directly activated by cAMP (Epac). Here we tested potential off-target effects of the Epac activator on blood platelet activation signalling. We found that the Epac analogue 8-pCPT-2'-O-Me-cAMP inhibits agonist-induced-GPCR-stimulated, but not collagen-stimulated, P-selectin surface expression on Epac1 deficient platelets. In human platelets, 8-pCPT-2'-O-Me-cAMP inhibited P-selectin expression elicited by the PKC activator PMA. This effect was abolished in the presence of the extracellular ADP scavenger system CP/CPK. In silico modelling of 8-pCPT-2'O-Me-cAMP binding into the purinergic platelet receptor P2Y12 revealed that the analogue docks similar to the P2Y12 antagonist 2MeSAMP. The 8-pCPT-2'-O-Me-cAMP analogue per se, did not provoke Rap 1 (Rap 1-GTP) activation or phosphorylation on the vasodilator-stimulated phosphoprotein (VASP) at Ser-157. In addition, the protein kinase A (PKA) antagonists Rp-cAMPS and Rp-8-Br-cAMPS failed to block the inhibitory effect of 8-pCPT-2'-O-Me-cAMP on thrombin- and TRAP-induced Rap 1 activation, thus suggesting that PKA is not involved. We conclude that the 8-pCPT-2'-O-Me-cAMP analogue is able to inhibit agonist-induced-GPCR-stimulated P-selectin independent from Epac1; the off-target effect of the analogue appears to be mediated by antagonistic P2Y12 receptor binding. This has implications when using cAMP analogues on specialised system involving such receptors. We found, however that the Epac agonist 8-Br-2'-O-Me-cAMP did not affect platelet activation at similar concentrations. Copyright © 2013 Elsevier Inc. All rights reserved.

Nano-hybrid carboxymethyl-hexanoyl chitosan modified with (3-aminopropyl)triethoxysilane for camptothecin delivery.

PubMed

Hsiao, Meng-Hsuan; Tung, Tsan-Hua; Hsiao, Chi-Sheng; Liu, Dean-Mo

2012-06-20

Silane-modified amphiphilic chitosan was synthesized by anchoring a silane coupling agent, (3-aminopropyl)triethoxysilane, to a novel amphiphilic carboxymethyl-hexanoyl chitosan (CHC). The chemical structure of this new organic-inorganic hybrid molecule was characterized by FTIR and 13C-, 29Si-nuclear magnetic resonance, while the structural evolution was examined using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and dynamic light scattering (DLS). Experimental results indicated a self-assembly behaviour of molecules into nanoparticles with a stable polygonal geometry, consisting of ordered silane layers of 6 nm in thickness. The self-assembly property was found to be influenced by chemical composition and concentration of silane incorporated, while the size can be varied by the amount of anchored silane. It was also demonstrated that such vesicle exhibited excellent cytocompatibility and cellular internalization capability in ARPE-19 cell line, and presented well-controlled encapsulation and release profiles for (S)-(+)-camptothecin. These unique properties render it as a potential drug delivery nanosystem. Copyright © 2012 Elsevier Ltd. All rights reserved.

Reaction of dehydropyrrolizidine alkaloids with valine and hemoglobin.

PubMed

Zhao, Yuewei; Wang, Shuguang; Xia, Qingsu; Gamboa da Costa, Gonçalo; Doerge, Daniel R; Cai, Lining; Fu, Peter P

2014-10-20

Pyrrolizidine alkaloid-containing plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids exert toxicity through metabolism to dehydropyrrolizidine alkaloids that bind to cellular protein and DNA, leading to hepatotoxicity, genotoxicity, and tumorigenicity. To date, it is not clear how dehydropyrrolizidine alkaloids bind to cellular constituents, including amino acids and proteins, resulting in toxicity. Metabolism of carcinogenic monocrotaline, riddelliine, and heliotrine produces dehydromonocrotaline, dehyroriddelliine, and dehydroheliotrine, respectively, as primary reactive metabolites. In this study, we report that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived valine (DHP-valine) adducts. For structural elucidation, DHP-valine adducts were derivatized with phenyl isothiocyanate (PITC) to DHP-valine-PITC products. After HPLC separation, their structures were characterized by mass spectrometry, UV-visible spectrophotometry, (1)H NMR, and (1)H-(1)H COSY NMR spectral analysis. Two DHP-valine-PITC adducts, designated as DHP-valine-PITC-1 and DHP-valine-PITC-3, had the amino group of valine linked to the C7 position of the necine base, and the other two DHP-valine-PITC products, DHP-valine-PITC-2 and DHP-valine-PITC-4, linked to the C9 position of the necine base. DHP-valine-PITC-1 was interconvertible with DHP-valine-PITC-3, and DHP-valine-PITC-2 was interconvertible with DHP-valine-PITC-4. Reaction of dehydroriddelliine and dehydroheliotrine with valine provided similar results. However, reaction of valine and dehydroretronecine (DHR) under similar experimental conditions did not produce DHP-valine adducts. Reaction of dehydromonocrotaline with rat hemoglobin followed by derivatization with PITC also generated the same four DHP-valine-PITC adducts. This represents the first full structural elucidation of

A new alkaloid from the fruit of Nandina domestica Thunb.

PubMed

Peng, Cai-Ying; Liu, Jian-Qun; Zhang, Rui; Shu, Ji-Cheng

2014-01-01

A new steroidal alkaloid, (20S,22R,24R)-24-ethyl-3-oxocholest-4-en-22-amino, named as nandsterine (1), together with 10 known alkaloids, palmatine (2), O-methylbulbocapnine (3), nantenine (4), dehydronantenine (5), glaucine (6), didehydroglaucine (7), dehydrocorydaline (8), jatrorrhizine (9), magnoflorine (10) and berberine (11), was isolated from the fruit of Nandina domestica Thunb. Their structures were elucidated by using spectroscopic methods as well as by comparing with the published data. Compound 1 was a new class of steroidal alkaloid isolated from the family Berberidaceae, meanwhile compounds 2, 3, 6-8 and 10 were obtained from N. domestica for the first time. Compound 1 exhibited cytotoxicity against HL-60 cells (human leukaemia) with IC50 values of 52.1 μM.

Alkaloid-Containing Plants Poisonous to Cattle and Horses in Europe.

PubMed

Cortinovis, Cristina; Caloni, Francesca

2015-12-08

Alkaloids, nitrogen-containing secondary plant metabolites, are of major interest to veterinary toxicology because of their occurrence in plant species commonly involved in animal poisoning. Based on epidemiological data, the poisoning of cattle and horses by alkaloid-containing plants is a relatively common occurrence in Europe. Poisoning may occur when the plants contaminate hay or silage or when forage alternatives are unavailable. Cattle and horses are particularly at risk of poisoning by Colchicum autumnale (meadow saffron), Conium maculatum (poison hemlock), Datura stramonium (jimson weed), Equisetum palustre (marsh horsetail), Senecio spp. (ragwort and groundsel) and Taxus baccata (European yew). This review of poisonous alkaloid-containing plants describes the distribution of these plants, conditions under which poisoning occurs, active toxic principles involved and subsequent clinical signs observed.

Alkaloid-Containing Plants Poisonous to Cattle and Horses in Europe

PubMed Central

Cortinovis, Cristina; Caloni, Francesca

2015-01-01

Alkaloids, nitrogen-containing secondary plant metabolites, are of major interest to veterinary toxicology because of their occurrence in plant species commonly involved in animal poisoning. Based on epidemiological data, the poisoning of cattle and horses by alkaloid-containing plants is a relatively common occurrence in Europe. Poisoning may occur when the plants contaminate hay or silage or when forage alternatives are unavailable. Cattle and horses are particularly at risk of poisoning by Colchicum autumnale (meadow saffron), Conium maculatum (poison hemlock), Datura stramonium (jimson weed), Equisetum palustre (marsh horsetail), Senecio spp. (ragwort and groundsel) and Taxus baccata (European yew). This review of poisonous alkaloid-containing plants describes the distribution of these plants, conditions under which poisoning occurs, active toxic principles involved and subsequent clinical signs observed. PMID:26670251

Hepatic β-Oxidation and Regulation of Carnitine Palmitoyltransferase (CPT) I in Blunt Snout Bream Megalobrama amblycephala Fed a High Fat Diet

PubMed Central

Lu, Kang-Le; Xu, Wei-Na; Wang, Li-Na; Zhang, Ding-Dong; Zhang, Chun-Nuan; Liu, Wen-Bin

2014-01-01

High-fat diets may promote growth, partly through their protein-sparing effects. However, high-fat diets often lead to excessive fat deposition, which may have a negative impact on fish such as poor growth and suppressive immune. Therefore, this study investigated the effects of a fat-rich diet on the mechanisms of fat deposition in the liver. Three-hundred blunt snout bream (Megalobrama amblycephala) juveniles (initial mass 18.00±0.05 g) were fed with one of two diets (5% or 15% fat) for 8 weeks. β-Oxidation capacity and regulation of rate-limiting enzymes were assessed. Large fat droplets were present in hepatocytes of fish fed the high-fat diet. This observation is thought to be largely owing to the reduced capacity for mitochondrial and peroxisomal β-oxidation in the livers of fish fed the high-fat diet, as well as the decreased activities of carnitine palmitoyltransferase (CPT) I and acyl-CoA oxidase (ACO), which are enzymes involved in fatty-acid metabolism. Study of CPT I kinetics showed that CPT I had a low affinity for its substrates and a low catalytic efficiency in fish fed the high-fat diet. Expression of both CPT I and ACO was significantly down-regulated in fish fed the high-fat diet. Moreover, the fatty-acid composition of the mitochondrial membrane varied between the two groups. In conclusion, the attenuated β-oxidation capacity observed in fish fed a high-fat diet is proposed to be owing to decreased activity and/or catalytic efficiency of the rate-limiting enzymes CPT I and ACO, via both genetic and non-genetic mechanisms. PMID:24676148

Eating chemically defended prey: alkaloid metabolism in an invasive ladybird predator of other ladybirds (Coleoptera: Coccinellidae).

PubMed

Sloggett, J J; Davis, A J

2010-01-15

By comparison with studies of herbivore physiological adaptation to plant allelochemicals, work on predator physiological adaptation to potentially toxic prey has been very limited. Such studies are important in understanding how evolution could shape predator diets. An interesting question is the specificity of predator adaptation to prey allelochemicals, given that many predators consume diverse prey with different chemical defences. The ladybird Harmonia axyridis, an invasive species in America, Europe and Africa, is considered a significant predatory threat to native invertebrates, particularly other aphid-eating ladybirds of which it is a strong intraguild predator. Although ladybirds possess species-specific alkaloid defences, H. axyridis exhibits high tolerance for allospecific ladybird prey alkaloids. Nonetheless, it performs poorly on species with novel alkaloids not commonly occurring within its natural range. We examined alkaloid fate in H. axyridis larvae after consumption of two other ladybird species, one containing an alkaloid historically occurring within the predator's native range (isopropyleine) and one containing a novel alkaloid that does not (adaline). Our results indicate that H. axyridis rapidly chemically modifies the alkaloid to which it has been historically exposed to render it less harmful: this probably occurs outside of the gut. The novel, more toxic alkaloid persists in the body unchanged for longer. Our results suggest metabolic alkaloid specialisation, in spite of the diversity of chemically defended prey that the predator consumes. Physiological adaptations appear to have made H. axyridis a successful predator of other ladybirds; however, limitations are imposed by its physiology when it eats prey with novel alkaloids.

Plant tropane alkaloid biosynthesis evolved independently in the Solanaceae and Erythroxylaceae

PubMed Central

Jirschitzka, Jan; Schmidt, Gregor W.; Reichelt, Michael; Schneider, Bernd; Gershenzon, Jonathan; D’Auria, John Charles

2012-01-01

The pharmacologically important tropane alkaloids have a scattered distribution among angiosperm families, like many other groups of secondary metabolites. To determine whether tropane alkaloids have evolved repeatedly in different lineages or arise from an ancestral pathway that has been lost in most lines, we investigated the tropinone-reduction step of their biosynthesis. In species of the Solanaceae, which produce compounds such as atropine and scopolamine, this reaction is known to be catalyzed by enzymes of the short-chain dehydrogenase/reductase family. However, in Erythroxylum coca (Erythroxylaceae), which accumulates cocaine and other tropane alkaloids, no proteins of the short-chain dehydrogenase/reductase family were found that could catalyze this reaction. Instead, purification of E. coca tropinone-reduction activity and cloning of the corresponding gene revealed that a protein of the aldo-keto reductase family carries out this reaction in E. coca. This protein, designated methylecgonone reductase, converts methylecgonone to methylecgonine, the penultimate step in cocaine biosynthesis. The protein has highest sequence similarity to other aldo-keto reductases, such as chalcone reductase, an enzyme of flavonoid biosynthesis, and codeinone reductase, an enzyme of morphine alkaloid biosynthesis. Methylecgonone reductase reduces methylecgonone (2-carbomethoxy-3-tropinone) stereospecifically to 2-carbomethoxy-3β-tropine (methylecgonine), and has its highest activity, protein level, and gene transcript level in young, expanding leaves of E. coca. This enzyme is not found at all in root tissues, which are the site of tropane alkaloid biosynthesis in the Solanaceae. This evidence supports the theory that the ability to produce tropane alkaloids has arisen more than once during the evolution of the angiosperms. PMID:22665766

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.

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease.

PubMed

Konrath, Eduardo Luis; Passos, Carolina dos Santos; Klein, Luiz Carlos; Henriques, Amélia T

2013-12-01

The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl- and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies. Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors. The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD. © 2013 Royal Pharmaceutical Society.

In vitro antiplasmodial, antiamoebic, and cytotoxic activities of some monomeric isoquinoline alkaloids.

PubMed

Wright, C W; Marshall, S J; Russell, P F; Anderson, M M; Phillipson, J D; Kirby, G C; Warhurst, D C; Schiff, P L

2000-12-01

Twenty-one alkaloids have been assessed for activities against Plasmodium falciparum (multidrug- resistant strain K1) in vitro; 18 of these are reported for the first time. Two protoberberine alkaloids, dehydrodiscretine and berberine, were found to have antiplasmodial IC(50) values less than 1 M, while seven alkaloids-allocrytopine, columbamine, dehydroocoteine, jatrorrhizine, norcorydine, thalifendine, and ushinsunine-had values between 1 and 10 M. These results are discussed in the context of structure-activity relationships. Compounds were also assessed for antiamoebic and cytotoxic activities, but none was significantly active except for berberine, which was moderately cytotoxic.

Detection of Pyrrolizidine Alkaloid DNA Adducts in Livers of Cattle Poisoned with Heliotropium europaeum.

PubMed

Fu, Peter P; Xia, Qingsu; He, Xiaobo; Barel, Shimon; Edery, Nir; Beland, Frederick A; Shimshoni, Jakob A

2017-03-20

Pyrrolizidine alkaloids are among the most common poisonous plants affecting livestock, wildlife, and humans. Exposure of humans and livestock to toxic pyrrolizidine alkaloids through the intake of contaminated food and feed may result in poisoning, leading to devastating epidemics. During February 2014, 73 mixed breed female beef cows from the Galilee region of Israel were accidently fed pyrrolizidine alkaloid contaminated hay for 42 days, resulting in the sudden death of 24 cows over a period of 63 days. The remaining cows were slaughtered 2.5 months after the last ingestion of the contaminated hay. In this study, we report the histopathological analysis of the livers from five of the slaughtered cows and quantitation of pyrrolizidine alkaloid-derived DNA adducts from their livers and three livers of control cows fed with feed free of weeds producing pyrrolizidine alkaloids. Histopathological examination revealed that the five cows suffered from varying degrees of bile duct proliferation, fibrosis, and megalocytosis. Selected reaction monitoring HPLC-ES-MS/MS analysis indicated that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts were formed in all five livers. The livers from the three control cows did not have any liver damage nor any indication of DHP-DNA adduct formed. These results confirm that the toxicity observed in these cattle was caused by pyrrolizidine alkaloid poisoning and that pyrrolizidine alkaloid-derived DNA adducts could still be detected and quantified in the livers of the chronically poisoned cows 2.5 months after their last exposure to the contaminated feed, suggesting that DHP-derived DNA adducts can serve as biomarkers for pyrrolizidine alkaloid exposure and poisoning.

Alkaloid Profiling as an Approach to Differentiate Lupinus garfieldensis, Lupinus sabinianus and Lupinus sericeus.

PubMed

Cook, Daniel; Lee, Stephen T; Pfister, James A; Stonecipher, Clint A; Welch, Kevin D; Green, Benedict T; Panter, Kip E

2012-01-01

Many species in the Lupinus genus are poorly defined morphologically, potentially resulting in improper taxonomic identification. Lupine species may contain quinolizidine and/or piperidine alkaloids that can be acutely toxic and/or teratogenic, the latter resulting in crooked calf disease. To identify characteristic alkaloid profiles of Lupinus sabinianus, L. garfieldensis and L. sericeus which would aid in discriminating these species from each other and from L. sulphureus. Quinolizidine and piperidine alkaloids were extracted from herbarium specimens and recent field collections of L. sabinianus, L. garfieldensis and L. sericeus. The alkaloid composition of each species was defined using GC-FID and GC-MS and compared using multivariate statistics. Each of the three species investigated contained a diagnostic chemical fingerprint composed of quinolizidine and/or piperidine alkaloids. The alkaloid profiles of Lupinus sabinianus, L. garfieldensis and L. sericeus can be used as a tool to discriminate these species from each other and L. sulphureus as long as one considers locality of the collection in the case of L. sabinianus. Published 2011. This article is a US Government work and is in the public domain in the USA.

Temporal and spatial variation in alkaloid levels in Achnatherum robustum, a native grass infected with the endophyte Neotyphodium.

PubMed

Faeth, Stanley H; Gardner, Dale R; Hayes, Cinnamon J; Jani, Andrea; Wittlinger, Sally K; Jones, Thomas A

2006-02-01

The native North American perennial grass Achnatherum robustum (Vasey) Barkworth [= Stipa robusta (Vasey) Scribn.] or sleepygrass is toxic and narcotic to livestock. The causative agents are alkaloidal mycotoxins produced from infections by a systemic and asexual Neotyphodium endophyte. Recent studies suggest that toxicity is limited across the range of sleepygrass in the Southwest USA. We sampled 17 populations of sleepygrass with varying distance from one focal population known for its high toxicity levels near Cloudcroft, NM, USA. For some, we sampled individual plants twice within the same growing season and over successive years (2001-2004). We also determined infection levels in each population. In general, all populations were highly infected, but infection levels were more variable near the focal population. Only infected plants within populations near the Cloudcroft area produced alkaloids. The ergot alkaloid, ergonovine, comprised the bulk of the alkaloids, with lesser amounts of lysergic and isolysergic acid amides and ergonovinine alkaloids. Levels of all alkaloids were positively correlated among individual plants within and between growing seasons. Infected plants that produced no alkaloids in 1 yr did not produce any alkaloids within the same growing season or in other years. Levels of alkaloids in sleepygrass populations declined with distance from the Cloudcroft population, although infection levels increased. Infected plants in populations in northern New Mexico and southern Colorado produced no alkaloids at all despite 100% infectivity. Our results suggest that only specific Neotyphodium haplotypes or specific Neotyphodium-grass combinations produce ergot alkaloids in sleepygrass. The Neotyphodium haplotype or host-endophyte combination that produces toxic levels of alkaloids appears restricted to one locality across the range of sleepygrass. Because of the wide variation in alkaloid levels among populations, interactions between the endophyte

Antibody binding of circulating ergot alkaloids in cattle grazing tall fescue.

PubMed

Hill, N S; Thompson, F N; Dawe, D L; Stuedemann, J A

1994-03-01

Direct evidence linking alkaloids found in endophyte-infected tall fescue forage with the livestock disorder known as fescue toxicosis is lacking. Physiologic effects of fescue toxicosis include reduced serum prolactin concentration in cattle. A monoclonal antibody specific to the lysergic moiety of ergot alkaloids was developed in mice after creating an immunogen by linking lysergol to human serum albumin. The antibody was specific to the lysergic moiety and, therefore, it cross-reacted with ergot alkaloids, lysergic acid, and lysergol. The antibody did not cross-react with alkaloid derivatives that had bromated or hydrogenated lysergic ring moieties. Fescue toxicosis conditions were elicited in yearling Angus steers by permitting them to graze endophyte-infected tall fescue containing > 650 micrograms/kg of ergovaline for 60 days. Passive immunization of steers by infusion of the monoclonal antibody increased serum prolactin concentration by 7 ng/ml, beginning immediately after infusion. Control steers did not respond to treatment with bovine serum albumin. Active immunization of yearling Angus heifers with immunogens containing lysergol or ergonovine linked to human serum albumin resulted in an antibody response.

Agrobacterium rhizogenes-mediated transformation: root cultures as a source of alkaloids.

PubMed

Sevón, Nina; Oksman-Caldentey, Kirsi-Marja

2002-10-01

Hairy roots, transformed with Agrobacterium rhizogenes, have been found to be suitable for the production of secondary metabolites because of their stable and high productivity in hormone-free culture conditions. A number of plant species including many medicinal plants have been successfully transformed with Agrobacterium rhizogenes. Transformed root cultures have also been found to be a potential source of high-value pharmaceuticals. In this article the most important alkaloids produced by hairy roots are summarised. Several different methods have been used to increase the alkaloid accumulation in hairy root cultures. The selection of high productive root lines based on somaclonal variation offers an interesting option to enhance the productivity. Elicitors and modification of culture conditions have been shown to increase the growth and the alkaloid production in some cases. Genetic engineering is a modern tool to regulate the secondary metabolism also in hairy roots. However, our knowledge on biosynthesis of many alkaloids is still poor. Only a limited number of enzymes and their respective genes which regulate the biosynthetic pathways are fully characterised.

Tropinone reductases, enzymes at the branch point of tropane alkaloid metabolism.

PubMed

Dräger, Birgit

2006-02-01

Two stereospecific oxidoreductases constitute a branch point in tropane alkaloid metabolism. Products of tropane metabolism are the alkaloids hyoscyamine, scopolamine, cocaine, and polyhydroxylated nortropane alkaloids, the calystegines. Both tropinone reductases reduce the precursor tropinone to yield either tropine or pseudotropine. In Solanaceae, tropine is incorporated into hyoscyamine and scopolamine; pseudotropine is the first specific metabolite on the way to the calystegines. Isolation, cloning and heterologous expression of both tropinone reductases enabled kinetic characterisation, protein crystallisation, and structure elucidation. Stereospecificity of reduction is achieved by binding tropinone in the respective enzyme active centre in opposite orientation. Immunolocalisation of both enzyme proteins in cultured roots revealed a tissue-specific protein accumulation. Metabolite flux through both arms of the tropane alkaloid pathway appears to be regulated by the activity of both enzymes and by their access to the precursor tropinone. Both tropinone reductases are NADPH-dependent short-chain dehydrogenases with amino acid sequence similarity of more than 50% suggesting their descent from a common ancestor. Putative tropinone reductase sequences annotated in plant genomes other that Solanaceae await functional characterisation.

Hybrid Monoterpenoid Indole Alkaloids Obtained as Artifacts from Rauvolfia tetraphylla.

PubMed

Gao, Yuan; Zhou, Dong-Sheng; Hai, Ping; Li, Yan; Wang, Fei

2015-10-01

Five new hybrid monoterpenoid indole alkaloids bearing an unusual 2,2-dimethyl-4-oxopiperidin-6-yl moiety, namely rauvotetraphyllines F-H (1, 3, 4), 17-epi-rauvotetraphylline F (2) and 21-epi-rauvotetraphylline H (5), were isolated from the aerial parts of Rauvolfia tetraphylla. Their structures were established by extensive spectroscopic analysis. The new alkaloids were evaluated for their cytotoxicity in vitro against five human cancer cell lines.

Dehydropyrrolizidine alkaloid toxicity, cytotoxicity, and carcinogenicity

USDA-ARS?s Scientific Manuscript database

Dehyro-pyrrolizidine alkaloid (PA)-containing plants compose about 5% of the world’s flowering plants and they commonly poison livestock, wildlife and humans. Previous work has produced considerable understanding of PA toxicity, species susceptibility, conditions and routes of exposure, toxin metab...

Anthelmintic, Antibacterial and Cytotoxicity Activity of Imidazole Alkaloids from Pilocarpus microphyllus Leaves.

PubMed

Rocha, Jefferson A; Andrade, Ivanilza M; Véras, Leiz M C; Quelemes, Patrick V; Lima, David F; Soares, Maria J S; Pinto, Pedro L S; Mayo, Simon J; Ivanova, Galya; Rangel, Maria; Correia, Manuela; Mafud, Ana Carolina; Mascarenhas, Yvonne P; Delerue-Matos, Cristina; de Moraes, Josué; Eaton, Peter; Leite, José R S A

2017-04-01

Pilocarpus microphyllus Stapf ex Wardlew (Rutaceae), popularly known as jaborandi, is a plant native to the northern and northeastern macroregions of Brazil. Several alkaloids from this species have been isolated. There are few reports of antibacterial and anthelmintic activities for these compounds. In this work, we report the antibacterial and anthelmintic activity of five alkaloids found in P. microphyllus leaves, namely, pilosine, epiisopilosine, isopilosine, epiisopiloturine and macaubine. Of these, only anthelmintic activity of one of the compounds has been previously reported. Nuclear magnetic resonance, HPLC and mass spectrometry were combined and used to identify and confirm the structure of the five compounds. As regards the anthelmintic activity, the alkaloids were studied using in vitro assays to evaluate survival time and damaged teguments for Schistosoma mansoni adult worms. We found epiisopilosine to have anthelmintic activity at very low concentrations (3.125 μg mL -1 ); at this concentration, it prevented mating, oviposition, reducing motor activity and altered the tegument of these worms. In contrast, none of the alkaloids showed antibacterial activity. Additionally, alkaloids displayed no cytotoxic effect on vero cells. The potent anthelmintic activity of epiisopilosine indicates the potential of this natural compound as an antiparasitic agent. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Alkaloid diversity in the leaves of Australian Flindersia (Rutaceae) species driven by adaptation to aridity.

PubMed

Robertson, Luke P; Hall, Casey R; Forster, Paul I; Carroll, Anthony R

2018-05-04

The genus Flindersia (Rutaceae) comprises 17 species of mostly Australian endemic trees. Although most species are restricted to rainforests, four have evolved to grow in semi-arid and arid environments. In this study, the leaf alkaloid diversity of rainforest and semi-arid/arid zone adapted Australian Flindersia were compared by LC/MS-MS and NMR spectroscopy. Contrary to expectations, Flindersia alkaloid diversity was strongly correlated with environmental aridity, where species predominating in drier regions produced more alkaloids than their wet rainforest congenerics. Rainforest species were also more chemically similar to each other than were the four semi-arid/arid zone species. There was a significant relationship between the presence of alkaloid structural classes and phylogenetic distance, suggesting that alkaloid profiles are influenced by both genetic and environmental factors. The results suggest that the radiation of Flindersia species out of the rainforest and into drier environments has promoted the evolution of unique alkaloid diversity. Plants growing in arid and semi-arid regions of Australia may represent an untapped source of undescribed specialised metabolites. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies, and Liver Disease.

PubMed

Edgar, John A; Molyneux, Russell J; Colegate, Steven M

2015-01-20

Large outbreaks of acute food-related poisoning, characterized by hepatic sinusoidal obstruction syndrome, hemorrhagic necrosis, and rapid liver failure, occur on a regular basis in some countries. They are caused by 1,2-dehydropyrrolizidine alkaloids contaminating locally grown grain. Similar acute poisoning can also result from deliberate or accidental consumption of 1,2-dehydropyrrolizidine alkaloid-containing herbal medicines, teas, and spices. In recent years, it has been confirmed that there is also significant, low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids in many countries due to consumption of common foods such as honey, milk, eggs, salads, and meat. The level of 1,2-dehydropyrrolizidine alkaloids in these foods is generally too low and too intermittent to cause acute toxicity. However, these alkaloids are genotoxic and can cause slowly developing chronic diseases such as pulmonary arterial hypertension, cancers, cirrhosis, and congenital anomalies, conditions unlikely to be easily linked with dietary exposure to 1,2-dehydropyrrolizidine alkaloids, especially if clinicians are unaware that such dietary exposure is occurring. This Perspective provides a comprehensive review of the acute and chronic toxicity of 1,2-dehydropyrrolizidine alkaloids and their potential to initiate certain chronic diseases, and suggests some associative considerations or indicators to assist in recognizing specific cases of diseases that may have resulted from dietary exposure to these hazardous natural substances. If it can be established that low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids is a significant cause of some of these costly and debilitating diseases, then this should lead to initiatives to reduce the level of these alkaloids in the food chain.

Lipid catabolism via CPT1 as a therapeutic target for prostate cancer

PubMed Central

Schlaepfer, Isabel R.; Rider, Leah; Rodrigues, Lindsey Ulkus; Gijón, Miguel A.; Pac, Colton T.; Romero, Lina; Cimic, Adela; Sirintrapun, S. Joseph; Glodé, L. Michael; Eckel, Robert H.; Cramer, Scott D.

2014-01-01

Prostate cancer (PCa) is the most commonly diagnosed malignancy among western men and accounts for the second leading cause of cancer-related deaths. PCa tends to grow slowly and recent studies suggest that it relies on lipid fuel more than on aerobic glycolysis. However, the biochemical mechanisms governing the relationships between lipid synthesis, lipid utilization, and cancer growth remain unknown. To address the role of lipid metabolism in PCa we have used Etomoxir and Orlistat, clinically safe drugs that block lipid oxidation and lipid synthesis/lipolysis, respectively. Etomoxir is an irreversible inhibitor of the carnitine palmitoyltransferase (CPT1) enzyme that decreases beta oxidation in the mitochondria. Combinatorial treatments using Etomoxir and Orlistat resulted in synergistic decreased viability in LNCaP, VCaP and patient-derived benign and PCa cells. These effects were associated with decreased androgen receptor (AR) expression, decreased mammalian target of Rapamycin (mTOR) signaling and increased caspase-3 activation. Knockdown of CPT1A enzyme in LNCaP cells resulted in decreased palmitate oxidation but increased sensitivity to Etomoxir, with inactivation of AKT kinase and activation of caspase-3. Systemic treatment with Etomoxir in nude nice resulted in decreased xenograft growth over 21 days, underscoring the therapeutic potential of blocking lipid catabolism to decrease PCa tumor growth. PMID:25122071

Plant alkaloids that cause developmental defects through the disruption of cholinergic neurotransmission

USDA-ARS?s Scientific Manuscript database

The exposure of a developing embryo or fetus to alkaloids from plants, plant products, or plant extracts has the potential to cause developmental defects in humans and animals. These defects may have multiple causes but those induced by piperidine and quinolizidine alkaloids arise from the inhibiti...

[Analysis and evaluation of alkaloids and flavonoids in flower of Sophora flavescens from Shanxi province].

PubMed

Zhang, Huang-Qin; Zhu, Zhen-Hua; Qian, Da-Wei; Weng, Ze-Bin; Guo, Sheng; Duan, Jin-Ao; Lei, Zhen-Hong; Li, An-Ping

2016-12-01

This study intends to explore the potential resource-orientedutilization value of the flower of Sophora flavescents by analyzing alkaloids and flavonoids in the flower of S. flavescens from Shanxi province. This study established a rapid UPLC-TQ-MS/MS method that is used for determination of seven alkaloids and seven flavonoids in the flower of S.flavescens. The different florescences all have the seven detected alkaloids such as cytisine, oxy-matrine, oxy-sophocarpine, sophoridine, N-methylcytisine, matrine, sophocarpine.The total contents of detected alkaloids are as follows: flower buds 1.47%, primal flowers 1.34%, full bloomed flowers 1.17%, faded flowers 1.01%. The top three contents of alkaloids are N-methylcytisine , oxy-sophocarpine and oxymatrine, accounting for about 83% of the total amount of detected alkaloids. All the samples in different florescences have the seven detected flavonoids such as rutin, luteolin, quercetin, isoquercitrin, trifolirhizin, kurarinone, and kushenol I. The total contents of detected alkaloids are as follows: flower buds 495.2 μg•g⁻¹, primal flowers 313.7 μg•g⁻¹, faded flowers 224.2 μg•g⁻¹, full bloomed flowers 193.0 μg•g⁻¹. The content of luteolinis relatively higher than other detected flavonoids, accounting for about 89%-94% of the total amount of detected flavonoids. The results indicated that the flower of S.flavescens could be an important material resource to obtain the resourceful alkaloids. This result can provide scientific basis for resource-oriented utilization and industrial development of the flower of S. flavescens. Copyright© by the Chinese Pharmaceutical Association.

A new spermidine macrocyclic alkaloid isolated from Gymnosporia arenicola leaf.

PubMed

da Silva, Gustavo; Martinho, Ana; Soengas, Raquel González; Duarte, Ana Paula; Serrano, Rita; Gomes, Elsa Teixeira; Silva, Olga

2015-10-01

The isolation and structural elucidation of a macrocyclic alkaloid, characterized by the presence of a 13-membered macrolactam ring containing a spermidine unit N-linked to a benzoyl group is hereby reported. The structure of this previously unknown spermidine alkaloid isolated from Gymnosporia arenicola (Celastraceae) leaves has been elucidated by (1)H and (13)C NMR spectroscopy (including bidimensional analysis) and further characterized by high-resolution mass spectrometry and polarimetry. A route for the biosynthesis of this new bioactive macrocycle is proposed and the cytotoxicity of the compound was evaluated against two ATCC cell lines - one normal-derived (MCF10A) and one cancer-derived cell line (MCF7) - using the MTT assay. The alkaloid revealed to be non-cytotoxic against both cell lines. The IC50 values from the cells were also determined. Copyright © 2015 Elsevier B.V. All rights reserved.

Three new alkaloids from Xylopia vielana and their antiinflammatory activities.

PubMed

Guo, Yi-Gong; Ding, Yun-He; Wu, Guo-Jing; Zhu, Sheng-Lan; Sun, Yuan-Fang; Yan, Shi-Kai; Qian, Feng; Jin, Hui-Zi; Zhang, Wei-Dong

2018-02-05

Three new aporphine alkaloids, xylopialoids A-C (1-3), along with three known aporphine alkioids (4-6) and three other known compounds (7-9) were isolated from the roots of Xylopia vielana. Among these three new aporphine alkaloids, xylopialoid C (3) showed a special carbamido group directly connected to the nitrogen. The chemical structures of these nine compounds were determined by a combination of 1D and 2D NMR, MS, CD spectrum and Cu Kα X-ray crystallographic analyses. All these six alkaloids were firstly tested for the inhibitory activities against the production of NO in RAW264.7 cells stimulated by lipopolysaccharide (LPS). Among these compounds, 4 showed a potential inhibitory activity against the production of nitric oxide with IC 50 value of 1.39 μM. Copyright © 2018. Published by Elsevier B.V.

Application of Liquid Chromatography/Ion Trap Mass Spectrometry Technique to Determine Ergot Alkaloids in Grain Products

PubMed Central

Szymczyk, Krystyna; Jędrzejczak, Renata; Roszko, Marek

2015-01-01

Summary A liquid chromatography/ion trap mass spectrometry-based method to determine six ergot alkaloids and their isomers is presented. The samples were cleaned on neutral alumina-based solid-phase extraction cartridges. The following method parameters were obtained (depending on the analyte and spiking level): method recovery from 63.0 to 104.6%, relative standard deviation below 18%, linear range from 1 to 325 µg/kg, linear correlation coefficient not less than 0.98. The developed analytical procedure was applied to determine the levels of ergot alkaloids in 65 samples of selected rye-based food products (flour – 34 samples, bran – 12 samples, rye – 18 samples, flakes – 1 sample). Measurable levels of alkaloids were found in majority of the analysed samples, particularly in rye flour. Additionally, alkaloids were determined in ergot sclerotia isolated from rye grains. Total content was nearly 0.01% (97.9 mg/kg). However, the alkaloid profile was dominated by ergocristine at 45.6% (44.7 mg/kg), an alkaloid not commonly found in the tested food products. Ergocorninine at 0.2% (0.2 mg/kg) was the least abundant alkaloid. PMID:27904328

Survival and development of Heliothis virescens (Lepidoptera: Noctuidae) larvae on isogenic tobacco lines with different levels of alkaloids.

PubMed

Jackson, D Michael; Johnson, A W; Stephenson, M G

2002-12-01

Levels of pyridine alkaloids were measured in 18 tobacco, Nicotiana tabacum L., entries from three parental isolines ('NC 95', 'SC 58', and 'Coker 139'), grown at Tifton, GA, Florence, SC, and Oxford, NC, in 1991. Levels of alkaloids in bud leaves (first fully unfolded leaf below the apical leaf bud) were negatively correlated to natural infestation ratings of tobacco budworm larvae, Heliothis virescens (F.), 7 wk after transplanting. For artificially infested bud leaves at Oxford, there was a significant negative correlation between levels of total alkaloids and larval weights after 1 wk of feeding. In 1992, four entries from the 'NC 95' isoline were grown at Oxford, and samples for alkaloid analyses were taken every 2 wk at several leaf positions on each plant. During weeks 4, 8, 12, and 16, second instar tobacco budworms were caged on individual, intact leaves inside perforated plastic bags in the field. The survival and development of tobacco budworm larvae after 1 wk were negatively correlated with levels of alkaloids at the various leaf positions. Larvae survived better and grew faster on the bud leaves of each entry where alkaloid levels were lower than they did on leaves further down the stalk where alkaloid levels were higher. More larvae survived on the lower leaves of the low alkaloid lines than on the lower leaves of the high alkaloid lines. Even moderate increases in pyridine alkaloids had negative effects on tobacco budworm survival and development. Nicotine constituted >97% of the pyridine alkaloids in the 'NC95' isoline each year.

Joint CPT and N resonance in compact atomic time standards

NASA Astrophysics Data System (ADS)

Crescimanno, Michael; Hohensee, Michael; Xiao, Yanhong; Phillips, David; Walsworth, Ron

2008-05-01

Currently development efforts towards small, low power atomic time standards use current-modulated VCSELs to generate phase-coherent optical sidebands that interrogate the hyperfine structure of alkali atoms such as rubidium. We describe and use a modified four-level quantum optics model to study the optimal operating regime of the joint CPT- and N-resonance clock. Resonant and non-resonant light shifts as well as modulation comb detuning effects play a key role in determining the optimal operating point of such clocks. We further show that our model is in good agreement with experimental tests performed using Rb-87 vapor cells.

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

Controlled drug delivery from composites of nanostructured porous silicon and poly(L-lactide).

PubMed

McInnes, Steven J P; Irani, Yazad; Williams, Keryn A; Voelcker, Nicolas H

2012-07-01

Porous silicon (pSi) and poly(L-lactide) (PLLA) both display good biocompatibility and tunable degradation behavior, suggesting that composites of both materials are suitable candidates as biomaterials for localized drug delivery into the human body. The combination of a pliable and soft polymeric material with a hard inorganic porous material of high drug loading capacity may engender improved control over degradation and drug release profiles and be beneficial for the preparation of advanced drug delivery devices and biodegradable implants or scaffolds. In this work, three different pSi and PLLA composite formats were prepared. The first format involved grafting PLLA from pSi films via surface-initiated ring-opening polymerization (pSi-PLLA [grafted]). The second format involved spin coating a PLLA solution onto oxidized pSi films (pSi-PLLA [spin-coated]) and the third format consisted of a melt-cast PLLA monolith containing dispersed pSi microparticles (pSi-PLLA [monoliths]). The surface characterization of these composites was performed via infrared spectroscopy, scanning electron microscopy, atomic force microscopy and water contact angle measurements. The composite materials were loaded with a model cytotoxic drug, camptothecin (CPT). Drug release from the composites was monitored via fluorimetry and the release profiles of CPT showed distinct characteristics for each of the composites studied. In some cases, controlled CPT release was observed for more than 5 days. The PLLA spin coat on pSi and the PLLA monolith containing pSi microparticles both released a CPT payload in accordance with the Higuchi and Ritger-Peppas release models. Composite materials were also brought into contact with human lens epithelial cells to determine the extent of cytotoxicity. We observed that all the CPT containing materials were highly efficient at releasing bioactive CPT, based on the cytotoxicity data.

Pharmacology of irinotecan.

PubMed

Kuhn, J G

1998-08-01

Irinotecan (CPT-11 [Camptosar]), a semisynthetic derivative of the plant alkaloid camptothecin, is bioactivated by carboxylesterases (EC3.1.1-) to the topoisomerase I inhibitor SN-38, a minor metabolite. Bioactivation of intravenously administered irinotecan by carboxylesterases occurs predominantly in the liver. Two human carboxylesterase isoforms responsible for SN-38 formation have been characterized. At relevant hepatic irinotecan concentrations up to 12 micrograms/mL, a low-Km isoform is responsible for irinotecan bioactivation. High concentrations of drugs commonly coadministered with irinotecan do not inhibit carboxylesterase activity. Intestinal carboxylesterases can also generate SN-38, followed by subsequent oral absorption. A second major polar metabolite of irinotecan, aminopentanecarboxylic acid (APC), is the product of CYP3A4-mediated oxidation of the terminal piperidine ring. APC is 100-fold less active than SN-38 as a topoisomerase I inhibitor and is a relatively weak inhibitor of acetylcholinesterase. SN-38 is eliminated mainly through conjugation by hepatic uridine glucuronosyltransferase (UGT*1.1), the same isoezyme responsible for glucuronidation of bilirubin. Grade 4 irinotecan-related toxicity (ie, neutropenia, diarrhea) has recently been reported in two patients with deficient UGT*1.1 activity. SN-38 glucuronide (SN-38G), which has only 1/100th the antitumor activity of SN-38, is actively secreted into the bile by a canalicular multispecific organic anion transporter. Deconjugation of SN-38G to SN-38 by beta-glucuronidase produced by the intestinal flora may contribute to enterohepatic recirculation of SN-38 and delayed intestinal toxicity.

Soil classification based on cone penetration test (CPT) data in Western Central Java

NASA Astrophysics Data System (ADS)

Apriyono, Arwan; Yanto, Santoso, Purwanto Bekti; Sumiyanto

2018-03-01

This study presents a modified friction ratio range for soil classification i.e. gravel, sand, silt & clay and peat, using CPT data in Western Central Java. The CPT data was obtained solely from Soil Mechanic Laboratory of Jenderal Soedirman University that covers more than 300 sites within the study area. About 197 data were produced from data filtering process. IDW method was employed to interpolated friction ratio values in a regular grid point for soil classification map generation. Soil classification map was generated and presented using QGIS software. In addition, soil classification map with respect to modified friction ratio range was validated using 10% of total measurements. The result shows that silt and clay dominate soil type in the study area, which is in agreement with two popular methods namely Begemann and Vos. However, the modified friction ratio range produces 85% similarity with laboratory measurements whereby Begemann and Vos method yields 70% similarity. In addition, modified friction ratio range can effectively distinguish fine and coarse grains, thus useful for soil classification and subsequently for landslide analysis. Therefore, modified friction ratio range proposed in this study can be used to identify soil type for mountainous tropical region.

Differences in Tolerance to Host Cactus Alkaloids in Drosophila koepferae and D. buzzatii

PubMed Central

Soto, Ignacio M.; Carreira, Valeria P.; Corio, Cristian; Padró, Julián; Soto, Eduardo M.; Hasson, Esteban

2014-01-01

The evolution of cactophily in the genus Drosophila was a major ecological transition involving over a hundred species in the Americas that acquired the capacity to cope with a variety of toxic metabolites evolved as feeding deterrents in Cactaceae. D. buzzatii and D. koepferae are sibling cactophilic species in the D. repleta group. The former is mainly associated with the relatively toxic-free habitat offered by prickly pears (Opuntia sulphurea) and the latter has evolved the ability to use columnar cacti of the genera Trichocereus and Cereus that contain an array of alkaloid secondary compounds. We assessed the effects of cactus alkaloids on fitness-related traits and evaluated the ability of D. buzzatii and D. koepferae to exploit an artificial novel toxic host. Larvae of both species were raised in laboratory culture media to which we added increasing doses of an alkaloid fraction extracted from the columnar cactus T. terschekii. In addition, we evaluated performance on an artificial novel host by rearing larvae in a seminatural medium that combined the nutritional quality of O. sulphurea plus amounts of alkaloids found in fresh T. terschekii. Performance scores in each rearing treatment were calculated using an index that took into account viability, developmental time, and adult body size. Only D. buzzatii suffered the effects of increasing doses of alkaloids and the artificial host impaired viability in D. koepferae, but did not affect performance in D. buzzatii. These results provide the first direct evidence that alkaloids are key determinants of host plant use in these species. However, the results regarding the artificial novel host suggest that the effects of alkaloids on performance are not straightforward as D. koepferae was heavily affected. We discuss these results in the light of patterns of host plan evolution in the Drosophila repleta group. PMID:24520377

tLyP-1-conjugated mesoporous silica nanoparticles for tumor targeting and penetrating hydrophobic drug delivery

NASA Astrophysics Data System (ADS)

Xu, Baiyao; Ju, Yang; Song, Guanbin; Cui, Yanbin

2013-12-01

Mesoporous silica nanoparticles (MSNs) are among the most appealing candidates for targeted drug delivery, a process for which it is essential that nanoparticles be internalized into targeted cells with high speed and efficiency. Therefore, it is necessary to conjugate a targeting ligand to the surface of a nanocarrier in order to trigger rapid receptor-mediated endocytosis and effective cellular uptake, which occurs following recognition and selective binding to a target cell's membrane receptor. Here, a tumor targeting and penetrating drug delivery system (DDS) based on MSNs ( 100 nm in size) is described. The MSNs were functionalized by engrafting with the tumor-homing and penetrating peptide tLyP-1. The fabricated MSN-tLyP-1 loaded with camptothecin (CPT) showed a robust targeting and penetrating efficiency to HeLa cells and MCF-7 cells and induced the death of these cells. Moreover, the adverse side effect of CPT on human mesenchymal stem cells (hMSCs) was minimized, because the nanoparticles were selectively targeted to the tumor cells, and little hydrophobic CPT was released into the culture medium or blood. The results indicate that the MSN-tLyP-1 DDS has great potential for the delivery of hydrophobic anticancer drugs to target tumors.

[Pyrrolizidine alkaloids and seneciosis in farm animals. Part 1: occurrence, chemistry and toxicology].

PubMed

Petzinger, E

2011-01-01

Pyrrolizidine alkaloids belong to a class of phytotoxins which are present in more than 6000 plant species. The disease seneciosis in farm animals represents the severe poisoning by pyrrolizidine alkaloids from plants of the genus Senecio. This form of poisoning has been known since the end of the 19th century in Germany, the USA, Canada and New Zealand, and is mainly caused by Senecio jacobaea and related Senecio spp. in farm animals, including poultry. Animal poisoning by pyrrolizidine alkaloids is of worldwide importance. In Germany poisoning of horses and cattle by Senecio jacobaea, which was earlier named Schweinsberg disease, is of renewed relevance for veterinary medicine. The disease occurs almost entirely as a consequence of chronic poisoning and in general ends fatally. The ultimate cause is the formation of toxic metabolites of pyrrolizidine alkaloids in the liver, and their covalent binding to nucleic acids and proteins leading to liver cirrhosis. Because many pyrrolizidine alkaloids possess mutagenic, and a few also carcinogenic properties, European and international authorities are concerned about possible residue levels in food of animal origin. The review addresses in its first part several aspects, being the occurrence, the chemistry, and the toxicology of pyrrolizidine alkaloids as well as animal intoxications by poisonous plants. In the second part (46) clinical characteristics of animal seneciosis, the therapeutic interventions, the significant species differences and a critical assessment of so-called nontoxic amounts of Senecio plants in animal fodder with reference to cumulative lethal toxin doses are presented.

The downregulation of the RNA-binding protein Staufen2 in response to DNA damage promotes apoptosis

PubMed Central

Zhang, Xin; Trépanier, Véronique; Beaujois, Remy; Viranaicken, Wildriss; Drobetsky, Elliot; DesGroseillers, Luc

2016-01-01

Staufen2 (Stau2) is an RNA-binding protein involved in cell fate decision by controlling several facets of mRNA processing including localization, splicing, translation and stability. Herein we report that exposure to DNA-damaging agents that generate replicative stress such as camptothecin (CPT), 5-fluoro-uracil (5FU) and ultraviolet radiation (UVC) causes downregulation of Stau2 in HCT116 colorectal cancer cells. In contrast, other agents such as doxorubicin and ionizing radiation had no effect on Stau2 expression. Consistently, Stau2 expression is regulated by the ataxia telangiectasia and Rad3-related (ATR) signaling pathway but not by the DNA-PK or ataxia telangiectasia mutated/checkpoint kinase 2 pathways. Stau2 downregulation is initiated at the level of transcription, independently of apoptosis induction. Promoter analysis identified a short 198 bp region which is necessary and sufficient for both basal and CPT-regulated Stau2 expression. The E2F1 transcription factor regulates Stau2 in untreated cells, an effect that is abolished by CPT treatment due to E2F1 displacement from the promoter. Strikingly, Stau2 downregulation enhances levels of DNA damage and promotes apoptosis in CPT-treated cells. Taken together our results suggest that Stau2 is an anti-apoptotic protein that could be involved in DNA replication and/or maintenance of genome integrity and that its expression is regulated by E2F1 via the ATR signaling pathway. PMID:26843428

Dynamic Variation Patterns of Aconitum Alkaloids in Daughter Root of Aconitum Carmichaelii (Fuzi) in the Decoction Process Based on the Content Changes of Nine Aconitum Alkaloids by HPLC- MS- MS

PubMed Central

Luo, Heng; Huang, Zhifang; Tang, Xiaolong; Yi, Jinhai; Chen, Shuiying; Yang, Andong; Yang, Jun

2016-01-01

The chemical components in the decoctions of Chinese herbal medicines are not always the same as those in the crude herbs because of the insolubility or instability of some compounds. In this work, a high-performance liquid chromatography (HPLC) coupled with electrospray ionization (ESI) tandem mass spectrometry method was developed to explore dynamic variation patterns of aconitum alkaloids in Fuzi during the process of decocting aconite root. The fragmentation patterns of aconitum alkaloids using ESI and collision-induced dissociation (CID) techniques were reported. This assay method was validated with respect to linearity (r2 > 0.9950), precision, repeatability, and accuracy (recovery rate between 94.6 and 107.9%).The result showed that the amounts of aconitum alkaloids in the decoction at different boiling time varied significantly. In the decoction process，the diester- type alkaloids in crude aconite roots have transformed into Benzoylaconines or aconines. PMID:27610167

Dynamic Variation Patterns of Aconitum Alkaloids in Daughter Root of Aconitum Carmichaelii (Fuzi) in the Decoction Process Based on the Content Changes of Nine Aconitum Alkaloids by HPLC- MS- MS.

PubMed

Luo, Heng; Huang, Zhifang; Tang, Xiaolong; Yi, Jinhai; Chen, Shuiying; Yang, Andong; Yang, Jun

2016-01-01

The chemical components in the decoctions of Chinese herbal medicines are not always the same as those in the crude herbs because of the insolubility or instability of some compounds. In this work, a high-performance liquid chromatography (HPLC) coupled with electrospray ionization (ESI) tandem mass spectrometry method was developed to explore dynamic variation patterns of aconitum alkaloids in Fuzi during the process of decocting aconite root. The fragmentation patterns of aconitum alkaloids using ESI and collision-induced dissociation (CID) techniques were reported. This assay method was validated with respect to linearity (r(2) > 0.9950), precision, repeatability, and accuracy (recovery rate between 94.6 and 107.9%).The result showed that the amounts of aconitum alkaloids in the decoction at different boiling time varied significantly. In the decoction process，the diester- type alkaloids in crude aconite roots have transformed into Benzoylaconines or aconines.

The Alkaloid Profiles of Lupinus sulphureus

USDA-ARS?s Scientific Manuscript database

Lupines are common plants found on the rangelands in the western United States. Lupines are known to 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 ...

Detection of Total Ergot Alkaloids in Cereal Flour and in Bread by a Generic Enzyme Immunoassay Method.

PubMed

Gross, Madeleine; Curtui, Valeriu; Usleber, Ewald

2018-05-01

Four sets of polyclonal antibodies against ergot alkaloids ergometrine, ergotamine, α-ergocryptine, and ergocornine were produced and characterized in a competitive direct or indirect enzyme immunoassay (EIA). Standard curve LODs were 0.03 ng/mL (ergometrine EIA) to 2.0 ng/mL (ergocornine EIA). Three EIAs were highly specific, whereas the ergometrine EIA had a broad specificity pattern and reacted, albeit weakly, with all seven major ergot alkaloids and their epimeric forms. Using the ergometrine EIA, a generic test system was established in which total ergot alkaloids are quantified by a standard curve for a toxin mixture composed of three alkaloids that matched the ergot alkaloid composition in naturally contaminated rye and wheat products. Sample extraction with acetonitrile-phosphate-buffered saline at pH 6.0 without further cleanup was sufficient for EIA analysis. The LODs for total ergot alkaloids were 20 ng/g in rye and wheat flour and 14 ng/g in bread. Recoveries were 85-110% (RSDs of 0.1-11.7%) at a concentration range of 50-1000 ng/g. The total ergot alkaloid EIA was validated by comparison with HPLC-fluorescence detection. Although some under- and overestimation by the total ergot alkaloid EIA was observed, it was suitable for the reliable identification of positive samples at 10-20 ng/g and for the determination of total ergot alkaloids in a concentration range between 100 and 1000 ng/g.

Towards a Molecular Understanding of the Biosynthesis of Amaryllidaceae Alkaloids in Support of Their Expanding Medical Use

PubMed Central

Takos, Adam M.; Rook, Fred

2013-01-01

The alkaloids characteristically produced by the subfamily Amaryllidoideae of the Amaryllidaceae, bulbous plant species that include well know genera such as Narcissus (daffodils) and Galanthus (snowdrops), are a source of new pharmaceutical compounds. Presently, only the Amaryllidaceae alkaloid galanthamine, an acetylcholinesterase inhibitor used to treat symptoms of Alzheimer’s disease, is produced commercially as a drug from cultivated plants. However, several Amaryllidaceae alkaloids have shown great promise as anti-cancer drugs, but their further clinical development is restricted by their limited commercial availability. Amaryllidaceae species have a long history of cultivation and breeding as ornamental bulbs, and phytochemical research has focussed on the diversity in alkaloid content and composition. In contrast to the available pharmacological and phytochemical data, ecological, physiological and molecular aspects of the Amaryllidaceae and their alkaloids are much less explored and the identity of the alkaloid biosynthetic genes is presently unknown. An improved molecular understanding of Amaryllidaceae alkaloid biosynthesis would greatly benefit the rational design of breeding programs to produce cultivars optimised for the production of pharmaceutical compounds and enable biotechnology based approaches. PMID:23727937

Recognition of pyrrolizidine alkaloid esters in the invasive aquatic plant Gymnocoronis spilanthoides (Asteraceae)

USDA-ARS?s Scientific Manuscript database

Introduction – The freshwater aquatic plant Gymnocoronis spilanthoides (Senegal tea plant, jazmín del bañado, Falscher Wasserfreund) is an invasive plant in many countries. Behavioural observations of pyrrolizidine alkaloid-pharmacophagous butterflies suggested the presence of pyrrolizidine alkaloid...

The effect of 7,8-methylenedioxylycoctonine-type diterpenoid alkaloids on the toxicity of methyllycaconitine in mice.

PubMed

Welch, K D; Panter, K E; Gardner, D R; Green, B T; Pfister, J A; Cook, D; Stegelmeier, B L

2008-10-01

Larkspur plants contain numerous norditerpenoid alkaloids, which include the 7,8-methylenedioxylycoctonine (MDL)-type alkaloids and the N-(methylsuccinimido)anthranoyllycoctonine (MSAL)-type alkaloids. The MSAL-type alkaloids are generally much more toxic (typically >20 times). Toxicity of many tall larkspurs, such as Delphinium barbeyi, has been attributed to its large concentration of MSAL-type alkaloids, including methyllycaconitine (MLA). However, the norditerpenoid alkaloids found in the greatest concentrations in most D. barbeyi populations are either deltaline or 14-O-acetyldictyocarpine (14-OAD), both less toxic MDL-type alkaloids. Although the individual toxicities of MLA, 14-OAD, and deltaline have been determined, the impact (additive or antagonistic) that large concentrations of deltaline or 14-OAD in the plant have on the toxicity of MLA is unknown. Consequently, the effect of MDL-type alkaloids on the toxicity of MLA was compared by using median lethal dose (LD(50)) and toxicokinetic profiles of the brainand muscle from mice receiving i.v. administration of these alkaloids, individually or in combination, at ratios of 1:1, 1:5, and 1:25 MLA to MDL-type alkaloids. The LD(50) for MLA alone was 4.4 +/- 0.7 mg/kg of BW, whereas the coadministration of MLA and deltaline at 1:1, 1:5, and 1:25 resulted in an LD(50) of 2.7, 2.5, and 1.9 mg/kg of BW, respectively. Similarly, the coadministration of MLA and 14-OAD at 1:1, 1:5, and 1:25 resulted in an LD(50) of 3.1, 2.2, and 1.5 mg/kg of BW, respectively. Coadministration of mixtures did not result in increased MLA bioavailability or alterations in clearance from the brain and muscle. Consequently, the increased toxicity of the mixtures was not a result of increased MLA bioavailability (based on the maximum concentrations observed) or alterations in MLA clearance from the brain and muscle, because these were unchanged. These results demonstrate that MDL-type alkaloids have an additive effect on MLA toxicity in

Aconitum alkaloid content and the high toxicity of aconite tincture.

PubMed

Chan, Thomas Y K

2012-10-10

Although proprietary medicines and decoction of processed aconite roots are the most widely used, tincture accounts for the great majority of aconite poisoning cases in China, indicating that it is much more toxic than other formulations. Aconite tincture is often self-prepared at home and raw aconite plants or roots are often used. Even if processed aconite roots were used to make the tincture, the amount of Aconitum alkaloids is highly variable, depending on the adequacy of processing and quality control. Aconitum alkaloids dissolve efficiently in alcohol. For these reasons, tincture contains very high concentrations of Aconitum alkaloids. Despite its high intrinsic toxicity, overdose of aconite tincture by the users has been common. Severe aconite poisoning can be complicated by fatal ventricular tachyarrhythmias and asystole. The public should be repeatedly warned of the danger of taking aconite tincture by mouth. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Marine Natural Product Bis-indole Alkaloid Caulerpin: Chemistry and Biology.

PubMed

Lunagariya, Jignesh; Bhadja, Poonam; Zhong, Shenghui; Vekariya, Rohit; Xu, Shihai

2017-09-27

Marine bis-indole alkaloids comprise a large and increasingly growing class of secondary metabolites, and continue to deliver a great variety of structural templates. The alkaloids derived from marine resources play a crucial role in medicinal chemistry and as chemical agents. In particular, bis-indole alkaloid caulerpin isolated from marine green algae Caulerpa and a red algae Chondria armata at various places around the world, and tested against several therapeutic areas such as anti-diabetic, antinociceptive, anti-inflammatory, anti-tumor, anti-larvicidal, anti-herpes, anti-tubercular, anti-microbial and immunostimulating activity as well as means of other chemical agents. Herein, we summarized discovery of caulerpin, and its potential medicinal and chemical applications in chronological order with various aspects. Additionally, synthesis of caulerpin, its functional analogues, and structural isomer have also been reviewed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Indole alkaloids of Psychotria as multifunctional cholinesterases and monoamine oxidases inhibitors.

PubMed

Passos, Carolina S; Simões-Pires, Claudia A; Nurisso, Alessandra; Soldi, Tatiane C; Kato, Lucilia; de Oliveira, Cecilia M A; de Faria, Emiret O; Marcourt, Laurence; Gottfried, Carmem; Carrupt, Pierre-Alain; Henriques, Amélia T

2013-02-01

Thirteen Psychotria alkaloids were evaluated regarding their interactions with acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A and MAO-B), which are enzymatic targets related with neurodegenerative diseases. Two quaternary β-carboline alkaloids, prunifoleine and 14-oxoprunifoleine, inhibited AChE, BChE and MAO-A with IC(50) values corresponding to 10 and 3.39 μM for AChE, 100 and 11 μM for BChE, and 7.41 and 6.92 μM for MAO-A, respectively. Both compounds seem to behave as noncompetitive AChE inhibitors and time-dependent MAO-A inhibitors. In addition, the monoterpene indole alkaloids (MIAs) angustine, vallesiachotamine lactone, E-vallesiachotamine and Z-vallesiachotamine inhibited BChE and MAO-A with IC(50) values ranging from 3.47 to 14 μM for BChE inhibition and from 0.85 to 2.14 μM for MAO-A inhibition. Among the tested MIAs, angustine is able to inhibit MAO-A in a reversible and competitive way while the three vallesiachotamine-like alkaloids display a time-dependent inhibition on this target. Docking calculations were performed in order to understand the binding mode between the most active ligands and the selected targets. Taken together, our findings established molecular details of AChE, BChE and MAO-A inhibition by quaternary β-carboline alkaloids and MIAs from Psychotria, suggesting these secondary metabolites are scaffolds for the development of multifunctional compounds against neurodegeneration. Copyright © 2012 Elsevier Ltd. All rights reserved.

Side-Effects of Irinotecan (CPT-11), the Clinically Used Drug for Colon Cancer Therapy, Are Eliminated in Experimental Animals Treated with Latex Proteins from Calotropis procera (Apocynaceae).

PubMed

de Alencar, Nylane Maria Nunes; da Silveira Bitencourt, Flávio; de Figueiredo, Ingrid Samantha Tavares; Luz, Patrícia Bastos; Lima-Júnior, Roberto César P; Aragão, Karoline Sabóia; Magalhães, Pedro Jorge Caldas; de Castro Brito, Gerly Anne; Ribeiro, Ronaldo Albuquerque; de Freitas, Ana Paula Fragoso; Ramos, Marcio Viana

2017-02-01

Intestinal mucositis (IM) is the critical side effect of irinotecan (CPT-11), which is the front-line drug used for the treatment of colorectal cancer. This study aimed to evaluate the effectiveness of latex proteins (LP) from Calotropis procera to prevent IM and diarrhea in animals. Swiss mice were treated daily with saline or LP (1, 5, or 50 mg/kg, i.v.) 24 h prior to CTP-11 (75 mg/kg/4 days, i.p) and for additional 6 days. Animal survival, body weight variation, and diarrhea were registered. After animal sacrifice (day 7 post first injection of CPT-11), intestinal samples were collected to study morphology and inflammatory parameters. Animals given LP exhibited improved parameters (survival, body weight, and absence of diarrhea) as compared with the CPT-11 control. The severity of IM observed in animals given CPT-11 was reduced in animals treated with LP. Treatment with LP also prevented the reduction in the villus/crypt ratio promoted by CPT-11. The rise in MPO activity and pro-inflammatory cytokines, over-contractility of the smooth muscle, and diarrhea were all abrogated in LP-treated mice. Markedly reduced immunostaining intensity for COX-2, TNF-α, IL-1β, iNOS, and NF-κB was observed in the intestinal tissue of animals treated with LP. The side-effects of CPT-11 were eliminated by LP treatment in experimental animals and improved clinical parameters characteristic of IM All known biochemical pathogenesis. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

POISONING OF CHICKENS AND DUCKS BY PYRROLIZIDINE ALKALOIDS OF HELIOTROPIUM EUROPAEUM.

PubMed

Pass, D A; Hogg, G G; Russell, R G; Edgar, J A; Tence, I M; Rikard-Bell, L

1979-05-01

The disease produced by feeding chickens and ducks a commercial poultry feed containing heliotrine and lasiocarpine, pyrrolizidine alkaloids of Heliotropium europaeum, is described. Illthrift, ascites and degenerative lesions in the liver were the major findings. Similar lesions occurred in chickens fed a diet containing H. europaeum. The source of the alkaloids in commercial poultry feed was probably the seeds of H. europaeum harvested with wheat.

A numerical similarity approach for using retired Current Procedural Terminology (CPT) codes for electronic phenotyping in the Scalable Collaborative Infrastructure for a Learning Health System (SCILHS).

PubMed

Klann, Jeffrey G; Phillips, Lori C; Turchin, Alexander; Weiler, Sarah; Mandl, Kenneth D; Murphy, Shawn N

2015-12-11

Interoperable phenotyping algorithms, needed to identify patient cohorts meeting eligibility criteria for observational studies or clinical trials, require medical data in a consistent structured, coded format. Data heterogeneity limits such algorithms' applicability. Existing approaches are often: not widely interoperable; or, have low sensitivity due to reliance on the lowest common denominator (ICD-9 diagnoses). In the Scalable Collaborative Infrastructure for a Learning Healthcare System (SCILHS) we endeavor to use the widely-available Current Procedural Terminology (CPT) procedure codes with ICD-9. Unfortunately, CPT changes drastically year-to-year - codes are retired/replaced. Longitudinal analysis requires grouping retired and current codes. BioPortal provides a navigable CPT hierarchy, which we imported into the Informatics for Integrating Biology and the Bedside (i2b2) data warehouse and analytics platform. However, this hierarchy does not include retired codes. We compared BioPortal's 2014AA CPT hierarchy with Partners Healthcare's SCILHS datamart, comprising three-million patients' data over 15 years. 573 CPT codes were not present in 2014AA (6.5 million occurrences). No existing terminology provided hierarchical linkages for these missing codes, so we developed a method that automatically places missing codes in the most specific "grouper" category, using the numerical similarity of CPT codes. Two informaticians reviewed the results. We incorporated the final table into our i2b2 SCILHS/PCORnet ontology, deployed it at seven sites, and performed a gap analysis and an evaluation against several phenotyping algorithms. The reviewers found the method placed the code correctly with 97 % precision when considering only miscategorizations ("correctness precision") and 52 % precision using a gold-standard of optimal placement ("optimality precision"). High correctness precision meant that codes were placed in a reasonable hierarchal position that a reviewer

8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation

PubMed Central

Jiao, Bo; Ren, Zhi-Hong; Liu, Ping; Chen, Li-Juan; Shi, Jing-Yi; Dong, Ying; Ablain, Julien; Shi, Lin; Gao, Li; Hu, Jun-Pei; Ren, Rui-Bao; de Thé, Hugues; Chen, Zhu; Chen, Sai-Juan

2013-01-01

The refractoriness of acute promyelocytic leukemia (APL) with t(11;17)(q23;q21) to all-trans retinoic acid (ATRA)-based therapy concerns clinicians and intrigues basic researchers. By using a murine leukemic model carrying both promyelocytic leukemia zinc finger/retinoic acid receptor-α (PLZF/RARα) and RARα/PLZF fusion genes, we discovered that 8-chlorophenylthio adenosine-3′, 5′-cyclic monophosphate (8-CPT-cAMP) enhances cellular differentiation and improves gene trans-activation by ATRA in leukemic blasts. Mechanistically, in combination with ATRA, 8-CPT-cAMP activates PKA, causing phosphorylation of PLZF/RARα at Ser765 and resulting in increased dissociation of the silencing mediator for retinoic acid and thyroid hormone receptors/nuclear receptor corepressor from PLZF/RARα. This process results in changes of local chromatin and transcriptional reactivation of the retinoic acid pathway in leukemic cells. Meanwhile, 8-CPT-cAMP also potentiated ATRA-induced degradation of PLZF/RARα through its Ser765 phosphorylation. In vivo treatment of the t(11;17) APL mouse model demonstrated that 8-CPT-cAMP could significantly improve the therapeutic effect of ATRA by targeting a leukemia-initiating cell activity. This combined therapy, which induces enhanced differentiation and oncoprotein degradation, may benefit t(11;17) APL patients. PMID:23382200

Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the clavicipitaceae reveals dynamics of alkaloid loci.

PubMed

Schardl, Christopher L; Young, Carolyn A; Hesse, Uljana; Amyotte, Stefan G; Andreeva, Kalina; Calie, Patrick J; Fleetwood, Damien J; Haws, David C; Moore, Neil; Oeser, Birgitt; Panaccione, Daniel G; Schweri, Kathryn K; Voisey, Christine R; Farman, Mark L; Jaromczyk, Jerzy W; Roe, Bruce A; O'Sullivan, Donal M; Scott, Barry; Tudzynski, Paul; An, Zhiqiang; Arnaoudova, Elissaveta G; Bullock, Charles T; Charlton, Nikki D; Chen, Li; Cox, Murray; Dinkins, Randy D; Florea, Simona; Glenn, Anthony E; Gordon, Anna; Güldener, Ulrich; Harris, Daniel R; Hollin, Walter; Jaromczyk, Jolanta; Johnson, Richard D; Khan, Anar K; Leistner, Eckhard; Leuchtmann, Adrian; Li, Chunjie; Liu, JinGe; Liu, Jinze; Liu, Miao; Mace, Wade; Machado, Caroline; Nagabhyru, Padmaja; Pan, Juan; Schmid, Jan; Sugawara, Koya; Steiner, Ulrike; Takach, Johanna E; Tanaka, Eiji; Webb, Jennifer S; Wilson, Ella V; Wiseman, Jennifer L; Yoshida, Ruriko; Zeng, Zheng

2013-01-01

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some-including the infamous ergot alkaloids-have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the

Oxidative stress and production of bioactive monoterpene indole alkaloids: biotechnological implications.

PubMed

Matsuura, Hélio Nitta; Rau, Mariana Ritter; Fett-Neto, Arthur Germano

2014-02-01

Monoterpene indole alkaloids (MIAs) encompass plant natural products with important pharmacological relevance. They include the anti-tumoral MIAs found in Catharanthus roseus and Camptotheca acuminata. The often low yields of bioactive alkaloids in plants has prompted research to identify the factors regulating MIA production. Oxidative stress is a general response associated with biotic and abiotic stresses leading to several secondary responses, including elicitation of MIA production. These changes in secondary metabolism may take place directly or via second messengers, such as Ca(2+) and reactive oxygen species (ROS). H2O2 is the main ROS that participates in MIA biosynthesis. This review analyzes the links between oxidative stress, elicitation of bioactive MIA production and their potential roles in antioxidant defense, as well as exploring the implications to developing biotechnological strategies relevant for alkaloid supply.

Alkaloids as important scaffolds in therapeutic drugs for the treatments of cancer, tuberculosis, and smoking cessation.

PubMed

Kittakoop, Prasat; Mahidol, Chulabhorn; Ruchirawat, Somsak

2014-01-01

Alkaloid molecules can act, depending on a type of amine functionality present in alkalods, as either hydrogenacceptor or hydrogen-donor for hydrogen bonding that is critically important for the interaction (binding) between targets (enzymes, proteins and receptors) and drugs (ligands). Because of this unique property, alkaloid scaffolds are therefore present in several drugs and lead compounds. This review highlights alkaloid scaffolds in drugs, particularly those recently approved in 2012; it also covers the scaffolds in leads and drug candidates which are in clinical trials and preclinical pipeline. The review focuses on three therapeutic areas including treatments of cancer, tuberculosis, and tobacco cessation. Alkaloid scaffolds in drugs and leads are inspired by those of naturally occurring alkaloids, and these scaffolds include pyridine, piperidine, quinoline, quinolinone, quinazoline, isoquinoline, indole, indolinone, isoindole, isoxazole, imidazole, indazole, thiazole, pyrazole, oxazolidinone, oxadiazole, and benzazepine. In addition to medicinal chemistry aspects, natural products possessing an individual alkaloid scaffold, as well as the mechanism of action of drugs and leads, are also discussed in this review.

Effects of nicotine and minor tobacco alkaloids on intracranial-self-stimulation in rats.

PubMed

Harris, Andrew C; Tally, Laura; Muelken, Peter; Banal, Andrew; Schmidt, Clare E; Cao, Qing; LeSage, Mark G

2015-08-01

While nicotine is the primary addictive compound in tobacco, other tobacco constituents including minor alkaloids (e.g., nornicotine, anabasine) may also contribute to tobacco addiction by mimicking or enhancing the effects of nicotine. Further evaluating the behavioral effects of minor alkaloids is essential for understanding their impact on tobacco addiction and informing development of tobacco product standards by the FDA. This study compared the addiction-related effects of nicotine and the minor alkaloids nornicotine, anabasine, myosmine, anatabine, and cotinine on intracranial self-stimulation (ICSS) thresholds in rats. Acute injection of nicotine produced reinforcement-enhancing (ICSS threshold-decreasing) effects at low to moderate doses, and reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high doses. Nornicotine and anabasine produced similar biphasic effects on ICSS thresholds, although with lower potency compared to nicotine. Myosmine only elevated ICSS thresholds at relatively high doses, while anatabine and cotinine did not influence ICSS thresholds at any dose. None of the alkaloids significantly influenced ICSS response latencies, indicating a lack of nonspecific motoric effects. These findings indicate that some minor tobacco alkaloids can either fully (nornicotine, anabasine) or partially (myosmine) mimic nicotine's addiction-related effects on ICSS, albeit at reduced potency. These findings emphasize the need for further study of the abuse potential of minor alkaloids, including evaluation of their effects when combined with nicotine and other tobacco constituents to better simulate tobacco exposure in humans. Such work is essential for informing FDA regulation of tobacco products and could also lead to the development of novel pharmacotherapies for tobacco addiction. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Variation in the expression of ergot alkaloids between individual tillers of perennial ryegrass

NASA Astrophysics Data System (ADS)

Mace, Wade; Lunn, Kristy; Lloyd-West, Catherine

2014-11-01

Epichloë fungal endophytes of cool season grasses are well known to produce a range of alkaloids of benefit to the host. Some of these compounds are advantageous to agriculture due to qualities that promote pasture persistence (e.g. the loline class of alkaloids confer insect protection) while others are detrimental to the wellbeing of grazing livestock. The ergot alkaloids (e.g. ergovaline), produced in ryegrass and tall fescue associations, causes poor animal health in farming regions in many countries around the world and further study is required to improve our knowledge on this class of compounds. Here we present the application of a quantitative LC-MS/MS (liquid chromatography coupled to mass spectrometry) method measuring eight ergot alkaloids (chanoclavine, agroclavine, elymoclavine, lysergol, lysergic acid, ergine, lysergyl alanine, ergovaline) produced by endophyte infected grasses, to monitor levels in individual tillers from multiple plants of a single cultivar of perennial ryegrass (Lolium perenne cv. ‘Grasslands Samson’) infected with a common toxic endophyte strain (Epichloë festucae var. lolii). Monitoring the expression in individual tillers allows an estimation of the variability within a plant (between tillers) as well as between plants. The study showed that there is significant variation in the concentration of the ergot alkaloids between tillers of a single plant, at or exceeding the level of variation observed between individual plants of a population. This result emphasizes the fundamental importance of robust experimental design and sampling procedures when alkaloid expression assessment is required and these need to be rigorously tailored to the hypothesis being tested.

TESTING FOR CPT VIOLATION IN B^{0_{s SEMILEPTONIC DECAYS}}

NASA Astrophysics Data System (ADS)

Kooten, R. Van

2014-01-01

A DØ analysis measuring the charge asymmetry A^{b_{sl of like-sign dimuon events due to semileptonic b-hadron decays at the Fermilab Tevatron Collider has shown indications of possible anomalous CP violation in the mixing of neutral B mesons. This result has been used to extract the first senstivity to CPT violation in the B0s system. An analysis to explore further this anomaly by specifically measuring the semileptonic charge asymmetry, assl, in B0s decays is described, as well as how a variant of this analysis can be used to explore a larger set of CPT-violating parameters in the B0s system for the first time.}}

Supercritical Fluid Extraction of Pyrrolidine Alkaloid from Leaves of Piper amalago L.

PubMed Central

Filho, L. C.; Faiões, V. S.; Cunha-Júnior, E. F.; Torres-Santos, E. C.; Cortez, D. A. G.

2017-01-01

Supercritical fluid extraction was used to extract the alkaloid N-[7-(3′,4′-methylenedioxyphenyl)-2(Z),4(Z)-heptadienoyl]pyrrolidine from leaves of Piper amalago L. A three-level orthogonal array design matrix, OAD OA9(34), was used for optimization of the parameters of supercritical extraction of the alkaloid, employing supercritical carbon dioxide: extraction time (20, 40, and 60 min), temperature (40, 50, and 60°C), pressure (150, 200, and 250 bar), and the use of cosolvents (ethanol, methanol, and propyleneglycol). All parameters had significant effect on the alkaloid yield. The alkaloid yield after 60 min of extraction without cosolvents at 9 different conditions (32) in terms of temperature (40, 50, and 60°C) and pressure (150, 200, and 250 bar) was also evaluated. The optimal yield (≈3.8 mg g−1) was obtained with supercritical CO2 + methanol (5% v : v) at 40°C and 200 bar for 60 min of extraction. PMID:28539966

Report on maloine, a new alkaloid discovered from G. maloi: Structural characterization and biological activity

NASA Astrophysics Data System (ADS)

Çela, Dorisa; Nepravishta, Ridvan; Lazari, Diamanto; Gaziano, Roberta; Moroni, Gabriella; Pica, Francesca; Paci, Maurizio; Abazi, Sokol

2017-02-01

Gymnospermium maloi Kit Tan, & Shuka is a new endemic species of the genus Gymnospermium Spach which has been described recently from the southern part of Albania. The members of this genus are poorly studied for what it concern the secondary metabolites in general and the class of alkaloids in particular. In fact from Gymnospermium genus, there are only few alkaloids characterized, (namely albertramine, albertidine, and albertine) isolated from G. albertii. Until now the chemical composition and the structure elucidation of other possible secondary metabolites, especially alkaloids, remain largely unknown. Here we report, for the first time, the structure of a new alkaloid isolated from G. maloi, designated by us as maloine, and obtained by the use of 2D homonuclear and heteronuclear NMR spectroscopy, FTIR, UV, Fluorescence and HPLC/MS spectra. The biological activity of the crude extract of Gymnospermium maloi and of its alkaloid maloine, was evaluated in vitro on human chronic myeloid leukemia cell line K562 and results herewith reported.

The toxicity of Poison Dart Frog alkaloids against the Fire Ant (Solenopsis invicta)

USDA-ARS?s Scientific Manuscript database

Hundreds of alkaloids, representing over 20 structural classes, have been identified from the skin of neotropical poison frogs (Dendrobatidae). These alkaloids are derived from arthropod prey of the frogs, and are generally are believed to deter vertebrate predators. We developed a method to put ind...

Tobacco alkaloids reduction by casings added/enzymatic hydrolysis treatments assessed through PLSR analysis.

PubMed

Lin, Shunshun; Zhang, Xiaoming; Song, Shiqing; Hayat, Khizar; Eric, Karangwa; Majeed, Hamid

2016-03-01

Based on encouraged development of potential reduced-exposure products (PREPs) by the US Institute of Medicine, casings (glucose and peptides) added treatments (CAT) and enzymatic (protease and xylanase) hydrolysis treatments (EHT) were developed to study their effect on alkaloids reduction in tobacco and cigarette mainstream smoke (MS) and further investigate the correlation between sensory attributes and alkaloids. Results showed that the developed treatments reduced nicotine by 14.5% and 24.4% in tobacco and cigarette MS, respectively, indicating that both CAT and EHT are potentially effective for developing lower-risk cigarettes. Sensory and electronic nose analysis confirmed the significant influence of treatments on sensory and cigarette MS components. PLSR analysis demonstrated that tobacco alkaloids were positively correlated to the off-taste, irritation and impact attributes, and negatively correlated to the aroma and softness attributes. Additionally, nicotine and anabasine from tobacco leaves positively contributed to the impact attribute, while they negatively contributed to the aroma attribute (P<0.05). Meanwhile, most alkaloids in cigarette MS positively contributed to the impact and irritation attributes (P<0.05). Hence, this study paved a way to better understand the correlation between tobacco alkaloids and sensory attributes. Copyright © 2015 Elsevier Inc. All rights reserved.

Urease and serine protease inhibitory alkaloids from Isatis tinctoria.

PubMed

Ahmad, Ijaz; Fatima, Itrat; Afza, Nighat; Malik, Abdul; Lodhi, Muhammad Arif; Choudhary, Muhammad Iqbal

2008-12-01

Phytochemical investigations on the alkaloidal fraction of the whole plant of the Isatis tinctoria led to the isolation of the alkaloids 1-6., 3'-Hydroxyepiglucoisatisin (3), Epiglucoisatisin (2) were found to be potent urease inhibitors in a concentration-dependent manner with IC(50) values 25.63 +/- 0.74, 37.01 +/- 0.41 and 31.72 +/- 0.93, 47.33 +/- 0.31 microM against Bacillus pasteurii & Jack bean urease, respectively. Compounds 3 and 2 also showed potent inhibitory potential against alpha-chymotrypsin with IC(50) values of 23.40 +/- 0.21 and 27.45 +/- 0.23 microM, respectively.

Butyrylcholinesterase, lipoxygenase inhibiting and antifungal alkaloids from Isatis tinctoria.

PubMed

Ahmad, Ijaz; Fatima, Itrat

2008-06-01

Phytochemical investigations on the alkaloidal fraction of the whole plant of the Isatis tinctoria led to the isolation of the alkaloids 1-6. Compounds 3, 2 were found to be potent butyrylcholinesterase and lipoxygenase enzymes inhibitors in a concentration-dependent manner with the IC(50) values 16.3 +/- 0.06 and 19.7 +/- 0.03 microM against BChE and 30.6 +/- 0.02 and 33.7 +/- 0.05 microM against LOX, respectively. The compounds (1-6) showed significant antifungal activity against Trichophyton schoen leinii, Aspergillus niger, Candida albicans, Trichophyton simii, and Macrophomina phaseolina.

Variation of the alkaloid content of Peumus boldus (boldo).

PubMed

Fuentes-Barros, Gonzalo; Castro-Saavedra, Sebastián; Liberona, Leonel; Acevedo-Fuentes, Williams; Tirapegui, Cristian; Mattar, César; Cassels, Bruce K

2018-06-01

Eighteen alkaloids were detected in the bark, leaves, wood and roots of Peumus boldus, including traces of secoboldine, N-methylsecoboldine (boldine methine), glaucine and norreticuline, not reported previously as constituents of this species. Using appropriate standards, we quantified thirteen of them by UHPLC-MS/MS. Boldine was dominant in the bark, and laurolitsine in wood and roots. The alkaloid composition of the leaves, determined for 130 individually identified trees, classified by age and sex, was highly variable, where N-methyllaurotetanine, laurotetanine, coclaurine and in some cases isocorydine predominated, but not boldine. Copyright © 2018 Elsevier B.V. All rights reserved.

Glutarimide alkaloids and a terpenoid benzoquinone from Cordia globifera.

PubMed

Parks, Joshua; Gyeltshen, Thinley; Prachyawarakorn, Vilailak; Mahidol, Chulabhorn; Ruchirawat, Somsak; Kittakoop, Prasat

2010-05-28

Three new compounds, a meroterpene (2) having a cyclopropane moiety named globiferane and glutarimide alkaloids named cordiarimides A (3) and B (4), were isolated from the roots of Cordia globifera. Compounds 2-4 exhibited weak cytotoxic activity. Cordiarimide B (4) exhibited radical scavenging activity, as it inhibited superoxide anion radical formation in the xanthine/xanthine oxidase (XXO) assay, and also suppressed superoxide anion generation in differentiated HL-60 human promyelocytic leukemia cells when induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). This is the first report on the presence of glutarimide alkaloids in the genus Cordia.

hERG Blockade by Iboga Alkaloids.

PubMed

Alper, Kenneth; Bai, Rong; Liu, Nian; Fowler, Steven J; Huang, Xi-Ping; Priori, Silvia G; Ruan, Yanfei

2016-01-01

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine's principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

New protopine alkaloids from Aristolochia constricta reduce morphine withdrawal in vitro.

PubMed

Capasso, A; De Tommasi, N; Rastrelli, L; De Simone, F

2000-12-01

The present study examines the effect of four new protopine alkaloids (1-4) isolated and purified from the aerial parts of Aristolochia constricta (Aristolichiaceae) on morphine withdrawal in vitro. The results of our experiments indicate that the pure compounds (1-4) significantly and in a concentration-dependent manner reduced the morphine withdrawal. The results of the present study suggest that these new protopine alkaloids may be potential anti-addictive agents.

Complicated hypertension related to the abuse of ephedrine and caffeine alkaloids.

PubMed

Berman, Jeffrey A; Setty, Arathi; Steiner, Matthew J; Kaufman, Kenneth R; Skotzko, Christine

2006-01-01

Ephedra containing products (ECPs), which most often contain additional sources of caffeine alkaloids, may be an under-recognized cause of hypertension. ECPs, especially when used in combination or at higher than recommended doses, can cause life-threatening cardiovascular and neurological complications. We present a case of hypertensive encephalopathy with new onset generalized tonic-clonic seizure secondary to concomitant use of two OTC supplements containing a mixture of ephedrine and caffeine alkaloids.

Effect of total alkaloids from Alstonia scholaris on airway inflammation in rats.

PubMed

Zhao, Yun-Li; Shang, Jian-Hua; Pu, Shi-Biao; Wang, Heng-Shan; Wang, Bei; Liu, Lu; Liu, Ya-Ping; Shen, Hong-Mei; Luo, Xiao-Dong

2016-02-03

Alstonia scholaris (Apocynaceae) have been traditionally used for treatment of respiratory diseases in "dai" ethnopharmacy for hundreds years, especially for cough, asthma, phlegm, chronic obstructive pulmonary disease and so on. The formulas including the leaf extract have also been prescribed in hospitals and sold over the retail pharmacies. A. scholaris is used as a traditional herbal medicine for the treatment of respiratory tract inflammation. However, there is no scientific evidence to validate the use of total alkaloids of A. scholaris in the literature. Here, we investigated the protective activity of total alkaloids (TA), extracted from the leaves of Alstonia scholaris, against lipopolysaccharide (LPS)-induced airway inflammation (AI) in rats. 200 μg/μL LPS was instilled intratracheally in each rat, and then the modeling animals were divided into six groups (n=10, each) randomly: sham group, LPS group, Dexamethasone [1.5mg/kg, intra-gastricly (i.g.)] group, and three different doses (7.5, 15, and 30 mg/kg, i.g.) of total alkaloids-treated groups. Corresponding drugs or vehicles were orally administered once per day for 7 days consecutively. The concentration of albumin (ALB), alkaline phosphatase (AKP), lactate dehydrogenase (LDH), and the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) were determined by fully automatic biochemical analyzer and blood counting instrument. Nitric oxide (NO) level, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activities were examined by multiskan spectrum, and histological change in the lungs was analyzed by H.E. staining. The levels of inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) were measured using ELISA. Total alkaloids decreased the percentage of neutrophil, number of WBC, levels of ALB, AKP and LDH in the BALF, while increased the content of ALB in serum. It also improved SOD activity and increased NO level in the lungs, serum and BALF, and

[Analysis of effect of topographical conditions on content of total alkaloid in Coptidis Rhizoma in Chongqin, China].

PubMed

Liu, Xin; Huang, He; Yang, Yan-fang; Wu, He-zhen

2014-12-01

To study ecology suitability rank dividing of the total alkaloid content of Coptis Rhizoma for selecting artificial planting base and high-quality industrial raw material in Chongqing province. Based on the investigation of PCB and DEM data of Chongqing province, the relationship between the total alkaloid content in Coptis Rhizoma and topographical conditions was analyzed by statistical analysis. The geographic information systems (GIS)-based assessment and landscape ecological principles were applied to assess eco logy suitability areas of Coptis Rhizoma in Chongqing. slope, aspect and altitude are main topographical factors that affect the content of the total alkaloid content in Coptis Rhizoma The total alkaloid content in Coptis Rhizoma is higher in the lower altitude, shady slope and bigger slope areas. The total alkaloid content is higher in the south areas of Chongqing province and lower in the northeast. Terrain conditions of the southern region of Chongqing are most suitable for The accumulated of total alkaloid Coptis Rhizoma content.

Piperidine alkaloids: Human and food animal teratogens

USDA-ARS?s Scientific Manuscript database

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...

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.

Inhibitory activities of the alkaloids from Coptidis Rhizoma against aldose reductase.

PubMed

Jung, Hyun Ah; Yoon, Na Young; Bae, Hyun Ju; Min, Byung-Sun; Choi, Jae Sue

2008-11-01

As part of our ongoing search of natural sources for therapeutic and preventive agents for diabetic complications, the rat lens aldose reductase (RLAR) inhibitory effect of Coptidis Rhizoma (the rhizome of Coptis chinensis Franch) was evaluated. Its extract and fractions exhibited broad and moderate RLAR inhibitory activities of 38.9 approximately 67.5 microg/mL. In an attempt to identify bioactive components, six quaternary protoberberine-type alkaloids (berberine, palmatine, jateorrhizine, epiberberine, coptisine, and groenlandicine) and one quaternary aporphine-type alkaloid (magnoflorine) were isolated from the most active n-BuOH fraction, and the chemical structures therein were elucidated on the basis of spectroscopic evidence and comparison with published data. The anti-diabetic complications capacities of seven C. chinensis-derived alkaloids were evaluated via RLAR and human recombinant AR (HRAR) inhibitory assays. Although berberine and palmatine were previously reported as prime contributors to AR inhibition, these two major components exhibited no AR inhibitory effects at a higher concentration of 50 microg/ml in the present study. Conversely, epiberberine, coptisine, and groenlandicine exhibited moderate inhibitory effects with IC(50) values of 100.1, 118.4, 140.1 microM for RLAR and 168.1, 187.3, 154.2 microM for HRAR. The results clearly indicated that the presence of the dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring were partly responsible for the AR inhibitory activities of protoberberine-type alkaloids. Therefore, Coptidis Rhizoma, and the alkaloids contained therein, would clearly have beneficial uses in the development of therapeutic and preventive agents for diabetic complications and diabetes mellitus.

Integration of Transcriptome, Proteome and Metabolism Data Reveals the Alkaloids Biosynthesis in Macleaya cordata and Macleaya microcarpa

PubMed Central

Liu, Fuqing; Huang, Peng; Zhu, Pengcheng; Chen, Jinjun; Shi, Mingming; Guo, Fang; Cheng, Pi; Zeng, Jing; Liao, Yifang; Gong, Jing; Zhang, Hong-Mei; Wang, Depeng; Guo, An-Yuan; Xiong, Xingyao

2013-01-01

Background The Macleaya spp., including Macleaya cordata and Macleaya microcarpa, are traditional anti-virus, inflammation eliminating, and insecticide herb medicines for their isoquinoline alkaloids. They are also known as the basis of the popular natural animal food addictive in Europe. However, few studies especially at genomics level were conducted on them. Hence, we performed the Macleaya spp. transcriptome and integrated it with iTRAQ proteome analysis in order to identify potential genes involved in alkaloids biosynthesis. Methodology and Principal Findings We elaborately designed the transcriptome, proteome and metabolism profiling for 10 samples of both species to explore their alkaloids biosynthesis. From the transcriptome data, we obtained 69367 and 78255 unigenes for M. cordata and M. microcarpa, in which about two thirds of them were similar to sequences in public databases. By metabolism profiling, reverse patterns for alkaloids sanguinarine, chelerythrine, protopine, and allocryptopine were observed in different organs of two species. We characterized the expressions of enzymes in alkaloid biosynthesis pathways. We also identified more than 1000 proteins from iTRAQ proteome data. Our results strongly suggest that the root maybe the organ for major alkaloids biosynthesis of Macleaya spp. Except for biosynthesis, the alkaloids storage and transport were also important for their accumulation. The ultrastructure of laticifers by SEM helps us to prove the alkaloids maybe accumulated in the mature roots. Conclusions/Significance To our knowledge this is the first study to elucidate the genetic makeup of Macleaya spp. This work provides clues to the identification of the potential modulate genes involved in alkaloids biosynthesis in Macleaya spp., and sheds light on researches for non-model medicinal plants by integrating different high-throughput technologies. PMID:23326424

Five new indole alkaloids from the leaves of Rauvolfia yunnanensis.

PubMed

Geng, Chang-An; Liu, Xi-Kui

2013-09-01

Five new indole alkaloids, rauvoloids A-E (1-5), together with two known ones, raucaffrinoline (6) and perakine (7) were isolated from the leaves of Rauvolfia yunnanensis. Their structures were elucidated by extensive spectroscopic methods. Structurally, rauvoloids A (1), B-C (2-3) and D (4) with unusual substitution patterns (no substitution, Cl and (1E)-3-oxo-butenyl, respectively) at C-20, are the first examples of perakine-type alkaloids with C18 and C22 skeletons. Copyright © 2013 Elsevier B.V. All rights reserved.

Therapeutic potential of songorine, a diterpenoid alkaloid of the genus Aconitum.

PubMed

Khan, Haroon; Nabavi, Seyed Mohammad; Sureda, Antoni; Mehterov, Nikolay; Gulei, Diana; Berindan-Neagoe, Ioana; Taniguchi, Hiroaki; Atanasov, Atanas G

2017-11-10

Alkaloids are well-studied secondary metabolites, with recent preclinical studies evidencing that many of them exhibit anti-cancer, anti-depressant, anti-nociceptive, anti-inflammatory, anti-pyretic, anti-platelet, anti-oxidant, and anti-bacterial properties. Aconitum is a genus rich of diverse alkaloids. More than 450 alkaloids have been identified in a variety of species. Songorine is a C 20 diterpenoid alkaloid and 12-keto analog of napelline, isolated from Aconitum soongaricum and was associated with a heterogeneous panel of biological functions. However, the bioactivity profile of this natural product has not been reviewed up to now. The present manuscript aims to summarize the most important biological activities associated with songorine administration in preclinical models. The most significant data found in the scientific literature were evaluated in order to summarize the potential clinical utility of songorine in a diverse spectrum of pathologies and conditions. Songorine and its derivatives have many pharmacological effects including anti-arrhythmic, anti-cardiac-fibrillation, excitation of synaptic transmission, anxiolytic effects, anti-nociceptive, anti-inflammatory, anti-arthritis effects, and a regenerative effect in a skin excision wound animal model. Despite its outstanding pharmacotherapeutic potential, songorine has never been tested in clinical trials. Therefore, further evaluation is required to better evaluate its clinical utility. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Identification and quantification of the main active anticancer alkaloids from the root of Glaucium flavum.

PubMed

Bournine, Lamine; Bensalem, Sihem; Wauters, Jean-Noël; Iguer-Ouada, Mokrane; Maiza-Benabdesselam, Fadila; Bedjou, Fatiha; Castronovo, Vincent; Bellahcène, Akeila; Tits, Monique; Frédérich, Michel

2013-12-02

Glaucium flavum is used in Algerian folk medicine to remove warts (benign tumors). Its local appellations are Cheqiq el-asfar and Qarn el-djedyane. We have recently reported the anti-tumoral activity of Glaucium flavum root alkaloid extract against human cancer cells, in vitro and in vivo. The principal identified alkaloid in the extract was protopine. This study aims to determine which component(s) of Glaucium flavum root extract might possess potent antitumor activity on human cancer cells. Quantitative estimation of Glaucium flavum alkaloids was realized by HPLC-DAD. Glaucium flavum effect on human normal and cancer cell viability was determined using WST-1 assay. Quantification of alkaloids in Glaucium flavum revealed that the dried root part contained 0.84% of protopine and 0.07% of bocconoline (w/w), while the dried aerial part contained only 0.08% of protopine, glaucine as the main alkaloid, and no bocconoline. In vitro evaluation of the growth inhibitory activity on breast cancer and normal cells demonstrated that purified protopine did not reproduce the full cytotoxic activity of the alkaloid root extract on cancer cell lines. On the other hand, bocconoline inhibited strongly the viability of cancer cells with an IC50 of 7.8 µM and only a low cytotoxic effect was observed against normal human cells. Our results showed for the first time that protopine is the major root alkaloid of Glaucium flavum. Finally, we are the first to demonstrate a specific anticancer effect of Glaucium flavum root extract against breast cancer cells, which can be attributed, at least in part, to bocconoline.

Model-based classification of CPT data and automated lithostratigraphic mapping for high-resolution characterization of a heterogeneous sedimentary aquifer

PubMed Central

Mallants, Dirk; Batelaan, Okke; Gedeon, Matej; Huysmans, Marijke; Dassargues, Alain

2017-01-01

Cone penetration testing (CPT) is one of the most efficient and versatile methods currently available for geotechnical, lithostratigraphic and hydrogeological site characterization. Currently available methods for soil behaviour type classification (SBT) of CPT data however have severe limitations, often restricting their application to a local scale. For parameterization of regional groundwater flow or geotechnical models, and delineation of regional hydro- or lithostratigraphy, regional SBT classification would be very useful. This paper investigates the use of model-based clustering for SBT classification, and the influence of different clustering approaches on the properties and spatial distribution of the obtained soil classes. We additionally propose a methodology for automated lithostratigraphic mapping of regionally occurring sedimentary units using SBT classification. The methodology is applied to a large CPT dataset, covering a groundwater basin of ~60 km2 with predominantly unconsolidated sandy sediments in northern Belgium. Results show that the model-based approach is superior in detecting the true lithological classes when compared to more frequently applied unsupervised classification approaches or literature classification diagrams. We demonstrate that automated mapping of lithostratigraphic units using advanced SBT classification techniques can provide a large gain in efficiency, compared to more time-consuming manual approaches and yields at least equally accurate results. PMID:28467468

Model-based classification of CPT data and automated lithostratigraphic mapping for high-resolution characterization of a heterogeneous sedimentary aquifer.

PubMed

Rogiers, Bart; Mallants, Dirk; Batelaan, Okke; Gedeon, Matej; Huysmans, Marijke; Dassargues, Alain

2017-01-01

Cone penetration testing (CPT) is one of the most efficient and versatile methods currently available for geotechnical, lithostratigraphic and hydrogeological site characterization. Currently available methods for soil behaviour type classification (SBT) of CPT data however have severe limitations, often restricting their application to a local scale. For parameterization of regional groundwater flow or geotechnical models, and delineation of regional hydro- or lithostratigraphy, regional SBT classification would be very useful. This paper investigates the use of model-based clustering for SBT classification, and the influence of different clustering approaches on the properties and spatial distribution of the obtained soil classes. We additionally propose a methodology for automated lithostratigraphic mapping of regionally occurring sedimentary units using SBT classification. The methodology is applied to a large CPT dataset, covering a groundwater basin of ~60 km2 with predominantly unconsolidated sandy sediments in northern Belgium. Results show that the model-based approach is superior in detecting the true lithological classes when compared to more frequently applied unsupervised classification approaches or literature classification diagrams. We demonstrate that automated mapping of lithostratigraphic units using advanced SBT classification techniques can provide a large gain in efficiency, compared to more time-consuming manual approaches and yields at least equally accurate results.

Phosphorylated Derivatives of Alkaloids and Nitrogen-containing Heterocycles — Cholinesterase Inhibitors

NASA Astrophysics Data System (ADS)

Sadykov, Abid S.; Dalimov, D. N.; Godovikov, Nikolai N.

1983-10-01

The review deals with the synthesis and anticholinesterase activities of phosphorylated derivatives of certain alkaloids and nitrogen-containing heterocycles. It is shown that the conformational properties of the alkaloid and nitrogen-containing heterocycle residues in the composition of the organophosphorus inhibitor (OPI) molecule play an important role in the inhibition of the catalytic activity of cholinesterases. The type of inhibition of cholinesterases also varies as a function of chemical structure. The bibliography includes 45 references.

Neopetrosiamine A, biologically active bis-piperidine alkaloid from the Caribbean Sea sponge Neopetrosia proxima

PubMed Central

Wei, Xiaomei; Nieves, Karinel; Rodríguez, Abimael D.

2010-01-01

A new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (1), has been extracted from the marine sponge Neopetrosia proxima collected off the west coast of Puerto Rico. The structure of compound 1 was elucidated by analysis of spectroscopic data coupled with careful comparisons of its 1H and 13C NMR data with those of a well-known 3-alkylbispiperidine alkaloid model. The new alkaloid displayed strong in vitro cytotoxic activity against a panel of cancer cell lines as well as in vitro inhibitory activity against the pathogenic microbes Mycobacterium tuberculosis and Plasmodium falciparum. PMID:20727745

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.

Unified Total Syntheses of Fawcettimine Class Alkaloids: Fawcettimine, Fawcettidine, Lycoflexine, and Lycoposerramine B

PubMed Central

Pan, Guojun; Williams, Robert M.

2012-01-01

The total syntheses of the lycopodium alkaloids: fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy, which relies on a Diels-Alder reaction to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary center. Access to the enantioselective syntheses of both antipodes of those alkaloids can be achieved by kinetic resolution of the earliest intermediate via a Sharpless asymmetric dihydroxylation (Sharpless AD). Compared to existing approaches to these alkaloids, our synthetic route possesses superior stereocontrol over the C-4 and C-15 stereogenic centers as well as allowing for more functional variation on the 6-membered ring. PMID:22519642

Extractions of isoquinoline alkaloids with butanol and octanol.

PubMed

Gregorová, Jana; Babica, Jan; Marek, Radek; Paulová, Hana; Táborská, Eva; Dostál, Jirí

2010-09-01

Six different isoquinoline alkaloids (sanguinarine, chelerythrine, berberine, coptisine, allocryptopine, and protopine) were extracted by butanol and octanol from aqueous solution, pH 4.5. The samples were analyzed by HPLC. Butanol extraction was non-selective, alkaloids passed into organic phase in 83-98%. Octanol extraction provided more selective yields: sanguinarine 99%, chelerythrine 94%, berberine 18%, coptisine 16%, allocryptopine 7.5%, protopine 7%. Further, we tested octanol treatment of extract from Dicranostigma lactucoides. The octanol extraction yields were also selective: sanguinarine 98%, chelerythrine 92%, chelirubine 92.5%, protopine 6% and allocryptopine 3.5%. 6-Butoxy-5,6-dihydrosanguinarine and 6-butoxy-5,6-dihydrochelerythrine were prepared and their NMR and MS data are reported and discussed. Copyright (c) 2010 Elsevier B.V. All rights reserved.

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.

Diversity in aconitine alkaloid profile of Aconitum plants in Hokkaido contrasts with their genetic similarity.

PubMed

Kakiuchi, Nobuko; Atsumi, Toshiyuki; Higuchi, Mari; Kamikawa, Shohei; Miyako, Haruka; Wakita, Yuriko; Ohtsuka, Isao; Hayashi, Shigeki; Hishida, Atsuyuki; Kawahara, Nobuo; Nishizawa, Makoto; Yamagishi, Takashi; Kadota, Yuichi

2015-01-01

Aconite tuber is a representative crude drug for warming the body internally in Japanese Kampo medicine and Chinese traditional medicine. The crude drug is used in major prescriptions for the aged. Varieties of Aconitum plants are distributed throughout the Japanese Islands, especially Hokkaido. With the aim of identifying the medicinal potential of Aconitum plants from Hokkaido, 107 specimens were collected from 36 sites in the summer of 2011 and 2012. Their nuclear DNA region, internal transcribed spacer (ITS), and aconitine alkaloid contents were analyzed. Phylogenic analysis of ITS by maximum parsimony analysis showed that the majority of the specimens were grouped into one cluster (cluster I), separated from the other cluster (cluster II) consisting of alpine specimens. The aconitine alkaloid content of the tuberous roots of 76 specimens showed 2 aspects-specimens from the same collection site showed similar aconitine alkaloid profiles, and cluster I specimens from different habitats showed various alkaloid profiles. Environmental pressure of each habitat is presumed to have caused the morphology and aconitine alkaloid profile of these genetically similar specimens to diversify.

Plant-Symbiotic Fungi as Chemical Engineers: Multi-Genome Analysis of the Clavicipitaceae Reveals Dynamics of Alkaloid Loci

PubMed Central

Schardl, Christopher L.; Young, Carolyn A.; Hesse, Uljana; Amyotte, Stefan G.; Andreeva, Kalina; Calie, Patrick J.; Fleetwood, Damien J.; Haws, David C.; Moore, Neil; Oeser, Birgitt; Panaccione, Daniel G.; Schweri, Kathryn K.; Voisey, Christine R.; Farman, Mark L.; Jaromczyk, Jerzy W.; Roe, Bruce A.; O'Sullivan, Donal M.; Scott, Barry; Tudzynski, Paul; An, Zhiqiang; Arnaoudova, Elissaveta G.; Bullock, Charles T.; Charlton, Nikki D.; Chen, Li; Cox, Murray; Dinkins, Randy D.; Florea, Simona; Glenn, Anthony E.; Gordon, Anna; Güldener, Ulrich; Harris, Daniel R.; Hollin, Walter; Jaromczyk, Jolanta; Johnson, Richard D.; Khan, Anar K.; Leistner, Eckhard; Leuchtmann, Adrian; Li, Chunjie; Liu, JinGe; Liu, Jinze; Liu, Miao; Mace, Wade; Machado, Caroline; Nagabhyru, Padmaja; Pan, Juan; Schmid, Jan; Sugawara, Koya; Steiner, Ulrike; Takach, Johanna E.; Tanaka, Eiji; Webb, Jennifer S.; Wilson, Ella V.; Wiseman, Jennifer L.; Yoshida, Ruriko; Zeng, Zheng

2013-01-01

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some—including the infamous ergot alkaloids—have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the

[Study on the separation process of pharmacological active total alkaloids from Chelidonium majus L. growing in Georgia].

PubMed

Bozhadze, A D; Vachnadze, V Iu; Dzhokhadze, M S; Berashvili, D T; Bakuridze, A Dzh

2013-04-01

In present article was studied the separation process of pharmacological active total alkaloids from Chelidonium majus L. growing in Georgia. Alkaloids were extracted from medicinal herbal material and separated by liquid extraction, diluents gas and a microfiltration through membrane equipment. The obtained A1, A2, A3 fractions were analyzed by GC/MS method; in all cases separation proceeds by the principle of extraction of the target alkaloids. It was concluded that the A1 is enriched with α and β cryptopins, and protopin, but homochelidonine and chelidonine are in low contents. As accompanying alkaloid is identified dihydrosanguinarine as an artifact; the A2 is enriched with the maximum contents of stylopine and protopin, but the poor contents of chelidonine and homochelidonine; the A3 is enriched with α and β cryptopins and maximum content of chelidonine. Extraction of alkaloids from Chelidonium majus L. proceeds selectively, but depending on a way of separation of the total alkaloids allows varying qualitative and quantitative consistence of the final product.

Smart particles for noble drug delivery system.

PubMed

Park, Cheolyoung; Kim, Jihoon; Jang, Seunghyun; Woo, Hee-Gweon; Ko, Young Chun; Sohn, Honglae

2010-05-01

Optically encoded smart particles were prepared for noble drug delivery materials. Distributed Bragg reflector (DBR) porous silicon (PSi) was generated by applying a computer-generated pseudo-square wave current waveform. This DBR PSi film was lifted off from the Si substrate and thermally oxidized to convert PSi to porous silicon dioxide (PSD). DBR PSD film was derivatized with 20(S)-Camptothecin (CPT) and fractured by ultrasono-method to give smart particles. DBR PSD smart particles exhibited a sharp photonic band gap in the optical reflectivity spectrum. Optical characteristic of PSD smart particles retained DBR photonic property in aqueous buffer solution. The release of CPT and change of reflection wavelength were measured by UV-vis and reflectance spectrometer, respectively. The intensity of differential peak from reflection resonances of the smart particles was increased with a drug release. The blue shift of reflection peak resulted in the decrease of refractive index of PSD smart particles during the drug release. The concentration of released drug exhibited an linear relationship with a release time.

Identification and Quantification of the Main Active Anticancer Alkaloids from the Root of Glaucium flavum

PubMed Central

Bournine, Lamine; Bensalem, Sihem; Wauters, Jean-Noël; Iguer-Ouada, Mokrane; Maiza-Benabdesselam, Fadila; Bedjou, Fatiha; Castronovo, Vincent; Bellahcène, Akeila; Tits, Monique; Frédérich, Michel

2013-01-01

Glaucium flavum is used in Algerian folk medicine to remove warts (benign tumors). Its local appellations are Cheqiq el-asfar and Qarn el-djedyane. We have recently reported the anti-tumoral activity of Glaucium flavum root alkaloid extract against human cancer cells, in vitro and in vivo. The principal identified alkaloid in the extract was protopine. This study aims to determine which component(s) of Glaucium flavum root extract might possess potent antitumor activity on human cancer cells. Quantitative estimation of Glaucium flavum alkaloids was realized by HPLC-DAD. Glaucium flavum effect on human normal and cancer cell viability was determined using WST-1 assay. Quantification of alkaloids in Glaucium flavum revealed that the dried root part contained 0.84% of protopine and 0.07% of bocconoline (w/w), while the dried aerial part contained only 0.08% of protopine, glaucine as the main alkaloid, and no bocconoline. In vitro evaluation of the growth inhibitory activity on breast cancer and normal cells demonstrated that purified protopine did not reproduce the full cytotoxic activity of the alkaloid root extract on cancer cell lines. On the other hand, bocconoline inhibited strongly the viability of cancer cells with an IC50 of 7.8 μM and only a low cytotoxic effect was observed against normal human cells. Our results showed for the first time that protopine is the major root alkaloid of Glaucium flavum. Finally, we are the first to demonstrate a specific anticancer effect of Glaucium flavum root extract against breast cancer cells, which can be attributed, at least in part, to bocconoline. PMID:24317429

Exposure to Ergot Alkaloids During Gestation Reduces Fetal Growth in Sheep

NASA Astrophysics Data System (ADS)

Duckett, Susan; Pratt, Scott; Andrae, John

2014-08-01

Tall fescue [Lolium arundinaceum (Schreb.) Darbysh; Schedonorus phoenix (Scop.) Holub] is the primary cool season perennial grass in the eastern U.S. Most tall fescue contains an endophyte (Neotyphodium coenophialum), which produces ergot alkaloids that cause vasoconstriction and could restrict blood flow to the fetus in pregnant animals. The objective of this study was to examine fetal growth during maternal exposure to ergot alkaloids during gestation. Pregnant ewes (n = 16) were randomly assigned to one of two dietary treatments: 1) endophyte-infected (Neotyphodium coenophialum) tall fescue seed (E+; 0.8 ug of ergovaline /g diet DM) and 2) endophyte-free tall fescue seed (E-; 0.0 ug of ergovaline/g diet DM). Birth weight of lambs was reduced by 37% for E+ compared to E-. Organ and muscle weights were also lighter for E+ than E-. Exposure to ergot alkaloids in utero reduces fetal growth and muscle development.

Effects of tryptophan derivatives and β-carboline alkaloids on radiation- and peroxide-induced transformations of ethanol

NASA Astrophysics Data System (ADS)

Sverdlov, R. L.; Brinkevich, S. D.; Shadyro, O. I.

2014-05-01

The subject of this study was investigation of interactions of tryptophan and its derivatives, including structurally related β-carboline alkaloids with oxygen- and carbon-centered radicals being formed during radiation- and peroxide-induced transformations of ethanol. It was shown that the above named compounds suppressed recombination and disproportionation reactions of α-hydroxyethyl radicals. The inhibitory effects of tryptophan, 5-hydroxytryptophan and serotonin were mainly realized by means of reduction and addition reactions, while those of β-carboline alkaloids - harmine, harmane and harmaline - were due to oxidation reactions. Melatonin displayed low reactivity towards α-hydroxyethyl radicals. Tryptophan derivatives and β-carboline alkaloids were found to inhibit radiation-induced oxidation of ethanol while being virtually not used up. The low transformation yields of tryptophan, 5-hydroxytryptophan and serotonin, as well as β-carboline alkaloids, indicate their capability of regeneration, which could occur on interaction of tryptophan with О-2 and НО2, or on oxidation of α-hydroxyethyl radicals by β-carboline alkaloids.

Newly discovered ergot alkaloids in Sorghum ergot Claviceps africana occurring for the first time in Israel.

PubMed

Shimshoni, J A; Cuneah, O; Sulyok, M; Krska, R; Sionov, E; Barel, S; Meller Harel, Y

2017-03-15

Sorghum ergot is a disease caused commonly by C. africana. In 2015, ergot was identified for the first time in sorghum fields in Israel, leading to measures of eradication and quarantine. The aims of the study were to identify the ergot species by molecular and ergot alkaloid profile analysis, to determine the ergot alkaloid profile in pure honeydew and in infected sorghum silages and to estimate the safety of sorghum silages as a feed source. C. africana was rapidly and reliably identified by microscopical and molecular analysis. Dihydroergosine was identified as the major ergot alkaloid. Dihydrolysergol and dihydroergotamine were identified for the first time as significant ergot alkaloid components within the C. africana sclerotia, thereby providing for the first time a proof for the natural occurrence of dihydroergotamine. The sorghum silages were found to be safe for feed consumption, since the ergot alkaloids and the regulated mycotoxins were below their regulated limits. Copyright © 2016 Elsevier Ltd. All rights reserved.

Determination of tropane alkaloids by heart cutting reversed phase - Strong cation exchange two dimensional liquid chromatography.

PubMed

Long, Zhen; Zhang, Yanhai; Gamache, Paul; Guo, Zhimou; Steiner, Frank; Du, Nana; Liu, Xiaoda; Jin, Yan; Liu, Xingguo; Liu, Lvye

2018-01-01

Current Chinese Pharmacopoeia (ChP) standards apply liquid extraction combined with one dimensional liquid chromatography (1DLC) method for determining alkaloids in herbal medicines. The complex pretreatments lead to a low analytical efficiency and possible component loss. In this study, a heart cutting reversed phase - strong cation exchange two dimensional liquid chromatography (RP - SCX 2DLC) approach was optimized for simultaneously quantifying tropane alkaloids (anisodine, scopolamine and hyoscyamine) in herbal medicines and herbal medicine tablets without further treatment of the filtered extract. The chromatographic conditions were systematically optimized in terms of column type, mobile phase composition and flow rate. To improve peak capacity and obtain symmetric peak shape of alkaloids, a polar group embedded C18 column combined with chaotropic salts was used in the first dimension. To remove the disturbance of non-alkaloids, achieve unique selectivity and acquire symmetric peak shape of alkaloids, an SCX column combined with phosphate buffer was used in the second dimension. Method validation was performed in terms of linearity, precision (0.54-0.82%), recovery (94.1-105.2%), limit of detection (LOD) and limit of quantification (LOQ) of the three analytes varied between 0.067-0.115mgL -1 and 0.195-0.268mgL -1 , respectively. The method demonstrated superiority over 1DLC method in respect of resolution (less alkaloid co-eluted), sample preparation (no pretreatment procedure) and transfer rate (minimum component loss). The optimized RP - SCX 2DLC approach was subsequently applied to quantify target alkaloids in five herbal medicines and herbal medicine tablets from three different manufactures. The results demonstrated that the developed heart cutting RP - SCX 2DLC approach represented a new, strategically significant methodology for the quality evaluation of tropane alkaloid in related herbal medicines that involve complex chemical matrix. Copyright �

In vitro characterization of transport and metabolism of the alkaloids: vincamine, vinpocetine and eburnamonine.

PubMed

Fandy, Tamer E; Abdallah, Inas; Khayat, Maan; Colby, David A; Hassan, Hazem E

2016-02-01

Vincamine, vinpocetine and eburnamonine are alkaloids known for their neuroprotective attributes, enhancement of cerebrovascular blood flow and antitumor effect of their derivatives. However, the relative metabolic stability of these alkaloids and their extrusion by the drug efflux transporters expressed at the blood-brain barrier (BBB) are not clear. In this study, we developed rapid and sensitive methods for the detection of these alkaloids and investigated their relative metabolic stability and their interaction with drug efflux transporters. UPLC methods were developed to analyze metabolic in vitro samples. Intrinsic clearance was determined using rat liver microsomal enzymes. Drug-stimulated transporter activity was estimated by measuring inorganic phosphate released from ATP spectrophotometrically. The UPLC methods quantification level ranged from 0.02 to 0.025 µg/mL, indicating high sensitivity. The intrinsic clearance of eburnamonine was significantly less than both vincamine and vinpocetine. Different concentrations of the three drugs (4, 20 and 100 µM) induced minimal stimulation of the ATPase activity of the Bcrp and Pgp membrane transporters. The developed simple, sensitive and reliable UPLC analysis methods can be utilized in future in vitro and in vivo studies. The three alkaloids demonstrated minimal interaction with the drug efflux transporters Pgp and Bcrp, concordant with the ability of these alkaloids to cross the BBB. The relative metabolic stability of eburnamonine compared to the other alkaloids suggests the use of eburnamonine or its derivatives as lead compounds for the development of antitumor and nootropic agents that need to cross the BBB and produce their pharmacological effects in the CNS.

Thin-Layer Chromatography/Desorption Electrospray Ionization Mass Spectrometry: Investigation of Goldenseal Alkaloids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Berkel, Gary J; Tomkins, Bruce A; Kertesz, Vilmos

2007-01-01

Desorption electrospray ionization mass spectrometry was investigated as a means to qualitatively identify and to quantify analytes directly from developed normal-phase thin layer chromatography plates. The atmospheric sampling capillary of a commercial ion trap mass spectrometer was extended to permit sampling and ionization of analytes in bands separated on intact TLC plates (up to 10 cm x 10 cm). A surface positioning software package and the appropriate hardware enabled computer-controlled surface scanning along the length of development lanes or at fixed RF value across the plates versus the stationary desorption electrospray emitter. Goldenseal (Hydrastis canadensis) and related alkaloids and commercialmore » dietary supplements were used as standards and samples. Alkaloid standards and samples were spotted and separated on aluminum- or glass-backed plates using established literature methods. The mass spectral signal levels as a function of desorption spray solvent were investigated with acetonitrile proving superior to methanol. The detection levels (ca. 5 ng each or 14 -28 pmol) in mass spectral full scan mode were determined statistically from the calibration curves (2.5 - 100 pmol) for the standards berberine, palmatine and hydrastinine spotted as a mixture and separated on the plates. Qualitative screening of the major alkaloids present in six different over-the-counter "goldenseal" dietary supplements was accomplished by obtaining full scan mass spectra during surface scans along the development lane in the direction of increasing RF value. In one sample, alkaloids were detected that strongly suggested the presence of at least one additional herb undeclared on the product label. These same data indicated the misidentification of one of the alkaloids in the TLC literature. Quantities of the alkaloids present in two of the samples determined using the mass spectral data were in reasonable agreement with the label values indicating the quantitative

Indolizidine 239Q and Quinolizidine 275I. Major alkaloids in two Argentinian bufonid toads (Melanophryniscus)

PubMed Central

Daly, John W.; Garraffo, H. Martin; Spande, Thomas F.; Yeh, Herman J. C.; Peltzer, Paola M.; Cacivio, Pedro; Baldo, J. Diego; Faivovich, Julián

2008-01-01

Alkaloid profiles in skin of poison frogs/toads (Dendrobatidae, Mantellidae, Bufonidae, and Myobatrachidae) are highly dependent on diet and hence on the nature of habitat. Extracts of the two species of toads (Melanophryniscus klappenbachi and M. cupreuscapularis) from similar habitats in the Corrientes/Chaco Provinces of Argentina have similar profiles of alkaloids, which differ considerably from profiles from other Melanophryniscus species from Brazil, Uruguay and Argentina. Structures of two major alkaloids 239Q (1) and 275I (2) were determined by mass, FTIR, and NMR spectral analysis as 5Z,9Z-3-(1-hydroxybutyl)-5-propylindolizidine and 6Z,10E-4,6-di(pent-4-enyl) quinolizidine, respectively. A third alkaloid, 249F (3), is postulated to be a homopumiliotoxin with an unprecedented conjugated exocyclic diene moiety. PMID:18848574

Opiate alkaloids antagonize postsynaptic glycine and GABA responses: correlation with convulsant action.

PubMed

Werz, M A; Macdonald, R L

1982-03-18

Opiate alkaloid and opioid peptide actions on spontaneous neuronal activity and postsynaptic amino acid responsiveness were assessed using intracellular recording techniques applied to murine spinal cord neurons in primary dissociated cell culture. Application of opiates was by superfusion and amino acids by iontophoresis. Glycine and GABA but not glutamate responses were antagonized by the opiate alkaloids. Since opiate effects on glycine and GABA responses were not naloxone-reversible, only weakly stereospecific, and not produced by the opioid peptide [D-Ala2]-Met-enkephalinamide, it is unlikely that these effects were mediated by opiate receptors. Opiate depression of glycine inhibition was correlated with the induction of paroxysmal depolarizations in cultured spinal cord neurons, suggesting that antagonism of inhibitory amino acid transmission may underlie the convulsant actions of high concentrations of the opiate alkaloids.

Neopetrosiamine A, biologically active bis-piperidine alkaloid from the Caribbean sea sponge Neopetrosia proxima.

PubMed

Wei, Xiaomei; Nieves, Karinel; Rodríguez, Abimael D

2010-10-01

A new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (1), has been extracted from the marine sponge Neopetrosiaproxima collected off the west coast of Puerto Rico. The structure of compound 1 was elucidated by analysis of spectroscopic data coupled with careful comparisons of its (1)H and (13)C NMR data with those of a well-known 3-alkylbis-piperidine alkaloid model. The new alkaloid displayed strong in vitro cytotoxic activity against a panel of cancer cell lines as well as in vitro inhibitory activity against the pathogenic microbes Mycobacterium tuberculosis and Plasmodium falciparum. Copyright © 2010 Elsevier Ltd. All rights reserved.

In Vitro Activities of Iboga Alkaloid Congeners Coronaridine and 18-Methoxycoronaridine against Leishmania amazonensis

PubMed Central

Delorenzi, Jan Carlo; Freire-de-Lima, Leonardo; Gattass, Cerli R.; de Andrade Costa, Deise; He, Liwen; Kuehne, Martin E.; Saraiva, Elvira M. B.

2002-01-01

In previous studies, we demonstrated the leishmanicide effect of coronaridine, a natural indole alkaloid isolated from stem bark of Peschiera australis (Delorenzi et al., Antimicrob. Agents Chemother. 45:1349-1354, 2001). In this study we show the leishmanicidal effect of the synthetic coronaridine and its racemic 18-methoxylated analog, 18-methoxycoronaridine. Both alkaloids revealed a potent leishmanicide effect against Leishmania amazonensis, a causative agent of cutaneous and diffuse cutaneous leishmaniasis in the New World. Despite their potent leishmanicide effect, both alkaloids were neither toxic to murine macrophages nor did they modulate their oxidative or cytokine production responses. PMID:12069962

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

Antitrichomonal activity of Peganum harmala alkaloid extract against trichomoniasis in pigeon (Columba livia domestica).

PubMed

Tabari, M A; Youssefi, M R; Moghadamnia, A A

2017-06-01

1. This study was designed to evaluate the antitrichomonal effects of P. harmala alkaloid extract against T. gallinae, both in vitro and in vivo, as well as comparing it to that of metronidazole, conventional antitrichomonal medication and harmine and harmaline, the two alkaloids present in P. harmala. 2. T. gallinae were collected by the wet mount method from infected free-living pigeons. The in vitro assay was performed using multi-well plates containing test compounds in final concentrations of 5, 10, 15, 20, 30, 50 or 100 μg/ml. The in vivo assay was done on 60 experimentally infected pigeons dosed with metronidazole at 50 mg/kg body weight (BW) or alkaloids at 25 mg/kg BW. 3. The 24 h minimum inhibitory concentration (MIC) of alkaloid extract was 15 µg/ml while that of metronidazole was 50 µg/ml. Harmine and harmaline revealed 24 h MIC of 30 and 100 µg/ml, respectively. Treatment of infected pigeons with alkaloids led to a full recovery after 3 d but with metronidazole total eradication of trophozoites was not achieved. 4. In conclusion, data of the present study suggested P. harmala is a potent natural anti-trichomonal agent, effective against T. gallinae.

Tandem Mass Spectrometry for Structural Identification of Sesquiterpene Alkaloids from the Stems of Dendrobium nobile Using LC-QToF.

PubMed

Wang, Yan-Hong; Avula, Bharathi; Abe, Naohito; Wei, Feng; Wang, Mei; Ma, Shuang-Cheng; Ali, Zulfiqar; Elsohly, Mahmoud A; Khan, Ikhlas A

2016-05-01

Dendrobium nobile is one of the fundamental herbs in traditional Chinese medicine. Sesquiterpene alkaloids are the main active components in this plant. Due to weak ultraviolet absorption and low content in D. nobile, these sesquiterpene alkaloids have not been extensively studied using chromatographic methods. Herein, tandem mass spectrometry combined with liquid chromatography separation provides a tool for the identification and characterization of the alkaloids from D. nobile. A total of nine sesquiterpene alkaloids were characterized by ultrahigh-performance liquid chromatography tandem mass spectrometry. These alkaloids can be classified into two subgroups that are represented by dendrobine and nobilonine. Tandem mass spectrometric studies revealed the fragmentation pathways of these two subgroup alkaloids that were used for the identification and characterization of other alkaloids in D. nobile. Characterization of these alkaloids using accurate mass and diagnostic fragments provided a reliable methodology for the analysis of D. nobile by ultrahigh-performance liquid chromatography tandem mass spectrometry. The limit of detection was defined as the signal-to-noise ratio equal to 3 : 1. Limits of detection of dendrobine and nobilonine were less than 30 ng/mL. The developed method was applied for the analysis of various Dendrobium species and related dietary supplements. Alkaloids were identified from D. nobile, but not detected from commercial samples including 13 other Dendrobium species and the 7 dietary supplements. Georg Thieme Verlag KG Stuttgart · New York.

Virtual-reality-based attention assessment of ADHD: ClinicaVR: Classroom-CPT versus a traditional continuous performance test.

PubMed

Neguț, Alexandra; Jurma, Anda Maria; David, Daniel

2017-08-01

Virtual-reality-based assessment may be a good alternative to classical or computerized neuropsychological assessment due to increased ecological validity. ClinicaVR: Classroom-CPT (VC) is a neuropsychological test embedded in virtual reality that is designed to assess attention deficits in children with attention deficit hyperactivity disorder (ADHD) or other conditions associated with impaired attention. The present study aimed to (1) investigate the diagnostic validity of VC in comparison to a traditional continuous performance test (CPT), (2) explore the task difficulty of VC, (3) address the effect of distractors on the performance of ADHD participants and typically-developing (TD) controls, and (4) compare the two measures on cognitive absorption. A total of 33 children diagnosed with ADHD and 42 TD children, aged between 7 and 13 years, participated in the study and were tested with a traditional CPT or with VC, along with several cognitive measures and an adapted version of the Cognitive Absorption Scale. A mixed multivariate analysis of covariance (MANCOVA) revealed that the children with ADHD performed worse on correct responses had more commissions and omissions errors than the TD children, as well as slower target reaction times . The results showed significant differences between performance in the virtual environment and the traditional computerized one, with longer reaction times in virtual reality. The data analysis highlighted the negative influence of auditory distractors on attention performance in the case of the children with ADHD, but not for the TD children. Finally, the two measures did not differ on the cognitive absorption perceived by the children.

Ergot and Its Alkaloids

PubMed Central

Schiff, Paul L.

2006-01-01

This manuscript reviews the history and pharmacognosy of ergot, and describes the isolation/preparation, chemistry, pharmacodynamics, and pharmacotherapeutics of the major ergot alkaloids and their derivatives. A brief discussion of the hallucinogenic properties of lysergic acid diethylamide is also featured. An abbreviated form of the material found in this paper is presented in a 4-hour didactic format to third-professional year PharmD students as part of their study of vascular migraine headaches, Parkinson's disease, and naturally occurring hallucinogens/hallucinogen derivatives in the modular course offering Neurology/Psychiatry. PMID:17149427

Micropropagation and validation of genetic and biochemical fidelity among regenerants of Nothapodytes nimmoniana (Graham) Mabb. employing ISSR markers and HPLC.

PubMed

Prakash, Lokesh; Middha, Sushil Kumar; Mohanty, Sudipta Kumar; Swamy, Mallappa Kumara

2016-12-01

An in vitro protocol has been established for clonal propagation of Nothapodytes nimmoniana which is an important source of Camptothecin (CPT). Elite source was identified based on the chemical potency to accumulate the optimum level of CPT. Different types and concentrations of plant growth regulators were used to study their effect on inducing multiple shoots from the explants regenerated from embryos of N. nimmoniana. Of these, a combination of N6-benzyladenine (0.2 mg L -1 ) and Indole-3-butyric acid (IBA) (0.1 mg L -1 ) proved optimum for differentiating multiple shoots in 90.6 % of the cultures with an average of 10.24 shoots per explant obtained within 8 weeks of inoculation. Nearly, 92 % of the excised in vitro shoots rooted on half strength Murashige and Skoog (MS) medium containing 0.05 % activated charcoal, supplemented with 1-naphthaleneacetic acid and IBA at 0.1 mg L -1 each. The micropropagated plants were evaluated for their genetic fidelity by employing inter simple sequence repeats (ISSR) markers. Ten individuals, randomly chosen from a population of 145 regenerants, were compared with the donor plant. The regenerated plants were also evaluated for their chemical potency using high-performance liquid chromatography (HPLC) analysis of CPT content. The true-to-type nature of the micropropagated plants was confirmed based on their monomorphic banding profiles with that of the mother plants using ISSR markers. Besides, HPLC evaluation of the CPT content confirmed the existence of chemical uniformity among the regenerated plants and the elite mother plant.

The downregulation of the RNA-binding protein Staufen2 in response to DNA damage promotes apoptosis.

PubMed

Zhang, Xin; Trépanier, Véronique; Beaujois, Remy; Viranaicken, Wildriss; Drobetsky, Elliot; DesGroseillers, Luc

2016-05-05

Staufen2 (Stau2) is an RNA-binding protein involved in cell fate decision by controlling several facets of mRNA processing including localization, splicing, translation and stability. Herein we report that exposure to DNA-damaging agents that generate replicative stress such as camptothecin (CPT), 5-fluoro-uracil (5FU) and ultraviolet radiation (UVC) causes downregulation of Stau2 in HCT116 colorectal cancer cells. In contrast, other agents such as doxorubicin and ionizing radiation had no effect on Stau2 expression. Consistently, Stau2 expression is regulated by the ataxia telangiectasia and Rad3-related (ATR) signaling pathway but not by the DNA-PK or ataxia telangiectasia mutated/checkpoint kinase 2 pathways. Stau2 downregulation is initiated at the level of transcription, independently of apoptosis induction. Promoter analysis identified a short 198 bp region which is necessary and sufficient for both basal and CPT-regulated Stau2 expression. The E2F1 transcription factor regulates Stau2 in untreated cells, an effect that is abolished by CPT treatment due to E2F1 displacement from the promoter. Strikingly, Stau2 downregulation enhances levels of DNA damage and promotes apoptosis in CPT-treated cells. Taken together our results suggest that Stau2 is an anti-apoptotic protein that could be involved in DNA replication and/or maintenance of genome integrity and that its expression is regulated by E2F1 via the ATR signaling pathway. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Bioresponsive polymer coated drug nanorods for breast cancer treatment

NASA Astrophysics Data System (ADS)

Laemthong, Tunyaboon; Kim, Hannah H.; Dunlap, Kelly; Brocker, Caitlin; Barua, Dipak; Forciniti, Daniel; Huang, Yue-Wern; Barua, Sutapa

2017-01-01

Ineffective drug release at the target site is among the top challenges for cancer treatment. This reflects the facts that interaction with the physiological condition can denature active ingredients of drugs, and low delivery to the disease microenvironment leads to poor therapeutic outcomes. We hypothesize that depositing a thin layer of bioresponsive polymer on the surface of drug nanoparticles would not only protect drugs from degradation but also allow the release of drugs at the target site. Here, we report a one-step process to prepare bioresponsive polymer coated drug nanorods (NRs) from liquid precursors using the solvent diffusion method. A thin layer (10.3 ± 1.4 nm) of poly(ε-caprolactone) (PCL) polymer coating was deposited on the surface of camptothecin (CPT) anti-cancer drug NRs. The mean size of PCL-coated CPT NRs was 500.9 ± 91.3 nm length × 122.7 ± 10.1 nm width. The PCL polymer coating was biodegradable at acidic pH 6 as determined by Fourier transform infrared spectroscopy. CPT drugs were released up to 51.5% when PCL coating dissolved into non-toxic carboxyl and hydroxyl groups. Trastuzumab (TTZ), a humanized IgG monoclonal antibody, was conjugated to the NR surface for breast cancer cell targeting. Combination treatments using CPT and TTZ decreased the HER-2 positive BT-474 breast cancer cell growth by 66.9 ± 5.3% in vitro. These results suggest effective combination treatments of breast cancer cells using bioresponsive polymer coated drug delivery.

Single cell subtractive transcriptomics for identification of cell-specifically expressed candidate genes of pyrrolizidine alkaloid biosynthesis.

PubMed

Sievert, Christian; Beuerle, Till; Hollmann, Julien; Ober, Dietrich

2015-09-01

Progress has recently been made in the elucidation of pathways of secondary metabolism. However, because of its diversity, genetic information concerning biosynthetic details is still missing for many natural products. This is also the case for the biosynthesis of pyrrolizidine alkaloids. To close this gap, we tested strategies using tissues that express this pathway in comparison to tissues in which this pathway is not expressed. As many pathways of secondary metabolism are known to be induced by jasmonates, the pyrrolizidine alkaloid-producing species Heliotropium indicum, Symphytum officinale, and Cynoglossum officinale of the Boraginales order were treated with methyl jasmonate. An effect on pyrrolizidine alkaloid levels and on transcript levels of homospermidine synthase, the first specific enzyme of pyrrolizidine alkaloid biosynthesis, was not detectable. Therefore, a method was developed by making use of the often observed cell-specific production of secondary compounds. H. indicum produces pyrrolizidine alkaloids exclusively in the shoot. Homospermidine synthase is expressed only in the cells of the lower leaf epidermis and the epidermis of the stem. Suggesting that the whole pathway of pyrrolizidine alkaloid biosynthesis might be localized in these cells, we have isolated single cells of the upper and lower epidermis by laser-capture microdissection. The resulting cDNA preparations have been used in a subtractive transcriptomic approach. Quantitative real-time polymerase chain reaction has shown that the resulting library is significantly enriched for homospermidine-synthase-coding transcripts providing a valuable source for the identification of further genes involved in pyrrolizidine alkaloid biosynthesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of ergot alkaloids associated with fescue toxicosis on hepatic cytochrome P450 and antioxidant proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Settivari, Raja S.; Evans, Tim J.; Rucker, Ed

Intake of ergot alkaloids found in endophyte-infected tall fescue grass is associated with decreased feed intake and reduction in body weight gain. The liver is one of the target organs of fescue toxicosis with upregulation of genes involved in xenobiotic metabolism and downregulation of genes associated with antioxidant pathways. It was hypothesized that short-term exposure of rats to ergot alkaloids would change hepatic cytochrome P450 (CYP) and antioxidant expression, as well as reduce antioxidant enzyme activity and hepatocellular proliferation rates. Hepatic gene expression of various CYPs, selected nuclear receptors associated with the CYP induction, and antioxidant enzymes were measured usingmore » real-time PCR. Hepatic expression of CYP, antioxidant and proliferating cell nuclear antigen (PCNA) proteins were measured using Western blots. The CYP3A1 protein expression was evaluated using primary rat hepatocellular cultures treated with ergovaline, one of the major ergot alkaloids produced by fescue endophyte, in order to assess the direct role of ergot alkaloids in CYP induction. The enzyme activities of selected antioxidants were assayed spectrophotometrically. While hepatic CYP and nuclear receptor expression were increased in ergot alkaloid-exposed rats, the expression and activity of antioxidant enzymes were reduced. This could potentially lead to increased oxidative stress, which might be responsible for the decrease in hepatocellular proliferation after ergot alkaloid exposure. This study demonstrated that even short-term exposure to ergot alkaloids can potentially induce hepatic oxidative stress which can contribute to the pathogenesis of fescue toxicosis.« less

Inducing Proactive Control Shifts in the AX-CPT

PubMed Central

Gonthier, Corentin; Macnamara, Brooke N.; Chow, Michael; Conway, Andrew R. A.; Braver, Todd S.

2016-01-01

The Dual Mechanisms of Control (DMC) account (Braver, 2012) proposes two distinct mechanisms of cognitive control, proactive and reactive. This account has been supported by a large number of studies using the AX-CPT paradigm that have demonstrated not only between-group differences, but also within-subjects variability in the use of the two control mechanisms. Yet there has been little investigation of task manipulations that can experimentally modulate the use of proactive control in healthy young adults; such manipulations could be useful to better understand the workings of cognitive control mechanisms. In the current study, a series of three experiments demonstrate how individuals can be systematically biased toward and away from the utilization of proactive control, via strategy training and no-go manipulations, respectively. These results provide increased support for the DMC framework, and provide a new basis from which to examine group-based differences and neural mechanisms underlying the two control modes. PMID:27920741

Determination of ephedrine alkaloids in botanicals and dietary supplements by HPLC-UV: collaborative study.

PubMed

Roman, Mark C

2004-01-01

An international collaborative study was conducted of a high-performance liquid chromatography (HPLC)-UV method for the determination of the major (ephedrine [EP] and pseudoephedrine [PS]) and minor (norephedrine [NE], norpseudoephedrine [NP], methylephedrine [ME], and methylpseudoephedrine [MP]) alkaloids in selected dietary supplements representative of the commercially available products. Ten collaborating laboratories determined the ephedrine-type alkaloid content in 8 blind replicate samples. Five products contained ephedra ground herb or ephedra extract. These 5 products included ground botanical raw material of Ephedra sinica, a common powdered extract of Ephedra sinica, a finished product containing only Ephedra sinica ground botanical raw material, a complex multicomponent dietary supplement containing Ma Huang, and a high-protein chocolate flavored drink mix containing Ma Huang extract. In addition, collaborating laboratories received a negative control and negative control spiked with ephedrine alkaloids at high and low levels for recovery studies. Test extracts were treated to solid-phase extraction using a strong-cation exchange column to help remove interferences. The HPLC analyses were performed on a polar-embedded phenyl column using UV detection at 210 nm. Repeatability relative standard deviations (RSDr) ranged from 0.64-3.0% for EP and 2.0-6.6% for PS, excluding the high protein drink mix. Reproducibility relative standard deviations (RSDR) ranged from 2.1-6.6% for EP and 9.0-11.4% for PS, excluding the high protein drink mix. Recoveries ranged from 84.7-87.2% for EP and 84.6-98.2% for PS. The data developed for the minor alkaloids are more variable with generally unsatisfactory HORRATS (i.e., >2). However, since these alkaloids generally add little to the total alkaloid content of the products, the method gives satisfactory results in measuring total alkaloid content (RSDr 0.85-3.13%; RSDR 2.03-10.97%, HORRAT 0.69-3.23, exclusive of the results

Pyridine-type alkaloid composition affects bacterial community composition of floral nectar

PubMed Central

Aizenberg-Gershtein, Yana; Izhaki, Ido; Santhanam, Rakesh; Kumar, Pavan; Baldwin, Ian T.; Halpern, Malka

2015-01-01

Pyridine-type alkaloids are most common in Nicotiana species. To study the effect of alkaloid composition on bacterial community composition in floral nectar, we compared the nicotine-rich wild type (WT) N. attenuata, the nicotine biosynthesis-silenced N. attenuata that was rich in anatabine and the anabasine-rich WT N. glauca plants. We found that the composition of these secondary metabolites in the floral nectar drastically affected the bacterial community richness, diversity and composition. Significant differences were found between the bacterial community compositions in the nectar of the three plants with a much greater species richness and diversity in the nectar from the transgenic plant. The highest community composition similarity index was detected between the two wild type plants. The different microbiome composition and diversity, caused by the different pyridine-type alkaloid composition, could modify the nutritional content of the nectar and consequently, may contribute to the change in the nectar consumption and visitation. These may indirectly have an effect on plant fitness. PMID:26122961

Pyridine-type alkaloid composition affects bacterial community composition of floral nectar.

PubMed

Aizenberg-Gershtein, Yana; Izhaki, Ido; Santhanam, Rakesh; Kumar, Pavan; Baldwin, Ian T; Halpern, Malka

2015-06-30

Pyridine-type alkaloids are most common in Nicotiana species. To study the effect of alkaloid composition on bacterial community composition in floral nectar, we compared the nicotine-rich wild type (WT) N. attenuata, the nicotine biosynthesis-silenced N. attenuata that was rich in anatabine and the anabasine-rich WT N. glauca plants. We found that the composition of these secondary metabolites in the floral nectar drastically affected the bacterial community richness, diversity and composition. Significant differences were found between the bacterial community compositions in the nectar of the three plants with a much greater species richness and diversity in the nectar from the transgenic plant. The highest community composition similarity index was detected between the two wild type plants. The different microbiome composition and diversity, caused by the different pyridine-type alkaloid composition, could modify the nutritional content of the nectar and consequently, may contribute to the change in the nectar consumption and visitation. These may indirectly have an effect on plant fitness.

[Isolation of the ergot (Claviceps purpurea (Fr.) Tul., strain VKM-F-366D), producing the lactamic alkaloid ergocornam].

PubMed

Komarova, E L; Shain, S S; Sheĭchenko, V I

2002-01-01

A new ergot strain VKM-F-3662D producing lactamic alkaloid ergocornam with concomitant alkaloids valinamide and ergometrine was isolated during selective works with sclerotium MS-462, which was obtained from ergocryptine ergot strain VKM-F-2642D. The structure of these alkaloids was determined by 1H and 13C NMR.

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.

Isoquinoline alkaloids and their binding with DNA: calorimetry and thermal analysis applications.

PubMed

Bhadra, Kakali; Kumar, Gopinatha Suresh

2010-11-01

Alkaloids are a group of natural products with unmatched chemical diversity and biological relevance forming potential quality pools in drug screening. The molecular aspects of their interaction with many cellular macromolecules like DNA, RNA and proteins are being currently investigated in order to evolve the structure activity relationship. Isoquinolines constitute an important group of alkaloids. They have extensive utility in cancer therapy and a large volume of data is now emerging in the literature on their mode, mechanism and specificity of binding to DNA. Thermodynamic characterization of the binding of these alkaloids to DNA may offer key insights into the molecular aspects that drive complex formation and these data can provide valuable information about the balance of driving forces. Various thermal techniques have been conveniently used for this purpose and modern calorimetric instrumentation provides direct and quick estimation of thermodynamic parameters. Thermal melting studies and calorimetric techniques like isothermal titration calorimetry and differential scanning calorimetry have further advanced the field by providing authentic, reliable and sensitive data on various aspects of temperature dependent structural analysis of the interaction. In this review we present the application of various thermal techniques, viz. isothermal titration calorimetry, differential scanning calorimetry and optical melting studies in the characterization of drug-DNA interactions with particular emphasis on isoquinoline alkaloid-DNA interaction.

The killer of Socrates: Coniine and Related Alkaloids in the Plant Kingdom.

PubMed

Hotti, Hannu; Rischer, Heiko

2017-11-14

Coniine, a polyketide-derived alkaloid, is poisonous to humans and animals. It is a nicotinic acetylcholine receptor antagonist, which leads to inhibition of the nervous system, eventually causing death by suffocation in mammals. Coniine's most famous victim is Socrates who was sentenced to death by poison chalice containing poison hemlock in 399 BC. In chemistry, coniine holds two historical records: It is the first alkaloid the chemical structure of which was established (in 1881), and that was chemically synthesized (in 1886). In plants, coniine and twelve closely related alkaloids are known from poison hemlock ( Conium maculatum L.), and several Sarracenia and Aloe species. Recent work confirmed its biosynthetic polyketide origin. Biosynthesis commences by carbon backbone formation from butyryl-CoA and two malonyl-CoA building blocks catalyzed by polyketide synthase. A transamination reaction incorporates nitrogen from l-alanine and non-enzymatic cyclization leads to γ-coniceine, the first hemlock alkaloid in the pathway. Ultimately, reduction of γ-coniceine to coniine is facilitated by NADPH-dependent γ-coniceine reductase. Although coniine is notorious for its toxicity, there is no consensus on its ecological roles, especially in the carnivorous pitcher plants where it occurs. Lately there has been renewed interest in coniine's medical uses particularly for pain relief without an addictive side effect.

Pharmacological and Toxicological Profile of Harmane-β-Carboline Alkaloid: Friend or Foe.

PubMed

Khan, Haroon; Patel, Seema; Kamal, Mohammad A

2017-01-01

The plant secondary metabolites have an outstanding therapeutic potential and success over the years. In fact, it is the foundation of numerous clinically used drugs. Similarly, these is a general perception that these products are inherent safety. However, such products might have toxic/unwanted lethal effects therefore, along with biological relevance, toxicological evaluation is equally important for clinical applications. Therefore, harmane- β-carboline alkaloid was investigated for both therapeutic and toxicological potential. The literature related to the therapeutic/toxicological effects of the alkaloid was searched using various scientific data bases including Google, ScienceDirect, PubMed, SpringerLink, ASC. The peer reviewed articles were only selected. The harmane-β-carboline alkaloid has shown several pharmacological activities such as antianxiety, antidepressant, antiplatelet, antidiabetic, acetylcholinesterase and myeloperoxidase inhibition, antioxidant, antiparasitic, hypotensive, morphine withdrawal syndrome alleviation, and antinociceptive effects. On the other hand, it exhibited tremorogenic effect, for a symptom of Parkinson's disease. Adverse effect of the alkaloid on learning and memory have also been observed. All together, it is, concluded in this review that harmane elicited marked pharmacological effects but simultaneously, it possessed some serious side effects that could be the primary hurdle in the way of its clinical testing. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Uncaria alkaloids reverse ABCB1-mediated cancer multidrug resistance

PubMed Central

Huang, Bao-Yuan; Zeng, Yu; Li, Ying-Jie; Huang, Xiao-Jun; Hu, Nan; Yao, Nan; Chen, Min-Feng; Yang, Zai-Gang; Chen, Zhe-Sheng; Zhang, Dong-Mei; Zeng, Chang-Qing

2017-01-01

The overexpression of ATP-binding cassette (ABC) transporters is the main cause of cancer multidrug resistance (MDR), which leads to chemotherapy failure. Uncaria alkaloids are the major active components isolated from uncaria, which is a common Chinese herbal medicine. In this study, the MDR-reversal activities of uncaria alkaloids, including rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine (Icory), hirsutine and hirsuteine, were screened; they all exhibited potent reversal efficacy when combined with doxorubicin. Among them, Icory significantly sensitized ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells to vincristine, doxorubicin and paclitaxel, but not to the non-ABCB1 substrate cisplatin. Noteworthy, Icory selectively reversed ABCB1-overexpressing MDR cancer cells but not ABCC1- or ABCG2-mediated MDR. Further mechanistic study revealed that Icory increased the intracellular accumulation of doxorubicin in ABCB1-overexpressing cells by blocking the efflux function of ABCB1. Instead of inhibiting ABCB1 expression and localization, Icory acts as a substrate of the ABCB1 transporter by competitively binding to substrate binding sites. Collectively, these results indicated that Icory reversed ABCB1-mediated MDR by suppressing its efflux function, and it would be beneficial to increase the efficacy of these types of uncaria alkaloids and develop them to be selective ABCB1-mediated MDR-reversal agents. PMID:28534954

Cpt1a gene expression in peripheral blood mononuclear cells as an early biomarker of diet-related metabolic alterations

PubMed Central

Díaz-Rúa, Rubén; Palou, Andreu; Oliver, Paula

2016-01-01

Background Research on biomarkers that provide early information about the development of future metabolic alterations is an emerging discipline. Gene expression analysis in peripheral blood mononuclear cells (PBMC) is a promising tool to identify subjects at risk of developing diet-related diseases. Objective We analysed PBMC expression of key energy homeostasis-related genes in a time-course analysis in order to find out early markers of metabolic alterations due to sustained intake of high-fat (HF) and high-protein (HP) diets. Design We administered HF and HP diets (4 months) to adult Wistar rats in isocaloric conditions to a control diet, mainly to avoid overweight associated with the intake of hyperlipidic diets and, thus, to be able to characterise markers of metabolically obese normal-weight (MONW) syndrome. PBMC samples were collected at different time points of dietary treatment and expression of relevant energy homeostatic genes analysed by real-time reverse transcription-polymerase chain reaction. Serum parameters related with metabolic syndrome, as well as fat deposition in liver, were also analysed. Results The most outstanding results were those obtained for the expression of the lipolytic gene carnitine palmitoyltransferase 1a (Cpt1a). Cpt1a expression in PBMC increased after only 1 month of exposure to both unbalanced diets, and this increased expression was maintained thereafter. Interestingly, in the case of the HF diet, Cpt1a expression was altered even in the absence of increased body weight but correlated with alterations such as higher insulin resistance, alteration of serum lipid profile and, particularly, increased fat deposition in liver, a feature characteristic of metabolic syndrome, which was even observed in animals fed with HP diet. Conclusions We propose Cpt1a gene expression analysis in PBMC as an early biomarker of metabolic alterations associated with MONW phenotype due to the intake of isocaloric HF diets, as well as a marker of

Self-assembled Nanomaterials for Chemotherapeutic Applications

NASA Astrophysics Data System (ADS)

Shieh, Aileen

The self-assembly of short designed peptides into functional nanostructures is becoming a growing interest in a wide range of fields from optoelectronic devices to nanobiotechnology. In the medical field, self-assembled peptides have especially attracted attention with several of its attractive features for applications in drug delivery, tissue regeneration, biological engineering as well as cosmetic industry and also the antibiotics field. We here describe the self-assembly of peptide conjugated with organic chromophore to successfully deliver sequence independent micro RNAs into human non-small cell lung cancer cell lines. The nanofiber used as the delivery vehicle is completely non-toxic and biodegradable, and exhibit enhanced permeability effect for targeting malignant tumors. The transfection efficiency with nanofiber as the delivery vehicle is comparable to that of the commercially available RNAiMAX lipofectamine while the toxicity is significantly lower. We also conjugated the peptide sequence with camptothecin (CPT) and observed the self-assembly of nanotubes for chemotherapeutic applications. The peptide scaffold is non-toxic and biodegradable, and drug loading of CPT is high, which minimizes the issue of systemic toxicity caused by extensive burden from the elimination of drug carriers. In addition, the peptide assembly drastically increases the solubility and stability of CPT under physiological conditions in vitro, while active CPT is gradually released from the peptide chain under the slight acidic tumor cell environment. Cytotoxicity results on human colorectal cancer cells and non-small cell lung cancer cell lines display promising anti-cancer properties compared to the parental CPT drug, which cannot be used clinically due to its poor solubility and lack of stability in physiological conditions. Moreover, the peptide sequence conjugated with 5-fluorouracil formed a hydrogel with promising topical chemotherapeutic applications that also display

Tolerating Toxins: Grasshoppers that Feast on Pyrrolizidine Alkaloids §.

PubMed

Housecroft, Catherine E

2018-03-30

The elegant grasshopper (Zonocerus elegans) and the variegated grasshopper (Z. variegatus) are among insects that deliberately consume and store pyrrolizidine alkaloids which are subsequently used in defence mechanisms.

An ignored cause of red urine in children: rhabdomyolysis due to carnitine palmitoyltransferase II (CPT-II) deficiency.

PubMed

Melek, Engin; Bulut, Fatma Derya; Atmış, Bahriye; Yılmaz, Berna Şeker; Bayazıt, Aysun Karabay; Mungan, Neslihan Önenli

2017-02-01

Carnitine palmitoyltransferase II (CPT-II) deficiency is an autosomal recessively inherited disorder involving the β-oxidation of long-chain fatty acids, which leads to rhabdomyolysis and subsequent acute renal failure. The clinical phenotype varies from a severe infantile form to a milder muscle form. Here, we report a 9-year-old boy referred to our hospital for the investigation of hematuria with a 2-day history of dark urine and malaise. As no erythrocytes in the microscopic examination of the urine and hemoglobinuria were present, myoglobinuria due to rhabdomyolysis was the most probable cause of dark urine. After excluding the other causes of rhabdomyolysis, with the help of metabolic investigations, the patient was suspected to have CPT-II deficiency, the most common cause of metabolic rhabdomyolysis. Our aim in presenting this case is to emphasize considering rhabdomyolysis in the differential diagnosis of dark urine in order to prevent recurrent rhabdomyolysis and renal injury.

An integrated strategy for the systematic characterization and discovery of new indole alkaloids from Uncaria rhynchophylla by UHPLC/DAD/LTQ-Orbitrap-MS.

PubMed

Pan, Huiqin; Yang, Wenzhi; Zhang, Yibei; Yang, Min; Feng, Ruihong; Wu, Wanying; Guo, Dean

2015-08-01

The exploration of new chemical entities from herbal medicines may provide candidates for the in silico screening of drug leads. However, this significant work is hindered by the presence of multiple classes of plant metabolites and many re-discovered structures. This study presents an integrated strategy that uses ultrahigh-performance liquid chromatography/linear ion-trap quadrupole/Orbitrap mass spectrometry (UHPLC/LTQ-Orbitrap-MS) coupled with in-house library data for the systematic characterization and discovery of new potentially bioactive molecules. Exploration of the indole alkaloids from Uncaria rhynchophylla (UR) is presented as a model study. Initially, the primary characterization of alkaloids was achieved using mass defect filtering and neutral loss filtering. Subsequently, phytochemical isolation obtained 14 alkaloid compounds as reference standards, including a new one identified as 16,17-dihydro-O-demethylhirsuteine by NMR analyses. The direct-infusion fragmentation behaviors of these isolated alkaloids were studied to provide diagnostic structural information facilitating the rapid differentiation and characterization of four different alkaloid subtypes. Ultimately, after combining the experimental results with a survey of an in-house library containing 129 alkaloids isolated from the Uncaria genus, a total of 92 alkaloids (60 free alkaloids and 32 alkaloid O-glycosides) were identified or tentatively characterized, 56 of which are potential new alkaloids for the Uncaria genus. Hydroxylation on ring A, broad variations in the C-15 side chain, new N-oxides, and numerous O-glycosides, represent the novel features of the newly discovered indole alkaloid structures. These results greatly expand our knowledge of UR chemistry and are useful for the computational screening of potentially bioactive molecules from indole alkaloids. Graphical Abstract A four-step integrated strategy for the systematic characterization and efficient discovery of new indole

Association of the CPT1B Gene with Skeletal Muscle Fat Infiltration in Afro-Caribbean Men

PubMed Central

Miljkovic, Iva; Yerges, Laura M.; Li, Hu; Gordon, Christopher L.; Goodpaster, Bret H.; Kuller, Lewis H.; Nestlerode, Cara S.; Bunker, Clareann H.; Patrick, Alan L.; Wheeler, Victor W.; Zmuda, Joseph M.

2010-01-01

Skeletal muscle fat is greater in African ancestry individuals compared with whites, is associated with diabetes, and is a heritable polygenic trait. However, specific genetic factors contributing to skeletal muscle fat in humans remain to be defined. Muscle carnitine palmitoyltransferase-1B (CPT1B) is a key enzyme in the regulation of skeletal muscle mitochondrial β-oxidation of long-chain fatty acids, and as such is a reasonable biological candidate gene for skeletal muscle fat accumulation. Therefore, we examined the association of three nonsynonymous coding variants in CPT1B (G531L, I66V, and S427C; a fourth, A320G, could not be genotyped) and quantitative computed tomography measured tibia skeletal muscle composition and BMI among 1,774 Afro-Caribbean men aged ≥40, participants of the population-based Tobago Health Study. For all variants, no significant differences were observed for BMI or total adipose tissue. Among individuals who were homozygous for the minor allele at G531L or I66V, intermuscular adipose tissue (IMAT) was 87% (P = 0.03) and 54% lower (P = 0.03), respectively. In contrast, subcutaneous adipose tissue (SAT) was 11% (P = 0.017) and 7% (P = 0.049) higher, respectively, than among individuals without these genotypes. These associations were independent of age, body size, and muscle area. Finally, no individuals with type 2 diabetes were found among those who were homozygous for the minor allele of either at G531L and I66V whereas 14–18% of men with the major alleles had type 2 diabetes (P = 0.03 and 0.007, respectively). Our results suggest a novel association between common nonsynonymous coding variants in CPT1B and ectopic skeletal muscle fat among middle-aged and older African ancestry men. PMID:19553926

Piperidine, pyridine alkaloid inhibition of fetal movement in a day 40 pregnant goat model.

PubMed

Green, Benedict T; Lee, Stephen T; Welch, Kevin D; Pfister, James A; Panter, Kip E

2013-08-01

Inhibition of fetal movement is one mechanism behind the development of multiple congenital contracture-type defects in developing fetuses of humans and animals. We tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alpha conotoxins EI and GI blockade at fetal muscle-type nicotinic acetylcholine receptors (nAChR) expressed by TE-671 cells. We also determined if the alkaloids decreased fetal movement in an IV dosed, day 40 pregnant goat model. In TE-671 cells, all three alkaloids elicited concentration-dependent changes in membrane potential sensing dye fluorescence. 1.0 μM alpha conotoxin GI shifted the concentration-effect curves of anabasine and myosmine to the right, and decreased maximal responses. Neither of the conotoxins blocked the actions of lobeline in TE-671 cells. In the day 40 pregnant goats, 0.8 mg/kg anabasine abolished fetal movement at 30 and 60 min after dosing and fetal movement was reduced by lobeline and myosmine. The blockade of anabasine and myosmine actions in TE-671 cells by alpha conotoxin GI indicates that they are agonists at fetal muscle-type nAChR. All three alkaloids did significantly decrease fetal movement in the day 40 pregnant goat model suggesting a potential for these alkaloids to cause multiple congenital contracture-type defects in developing fetuses. Published by Elsevier Ltd.

Ergot alkaloid intoxication in perennial ryegrass (Lolium perenne): an emerging animal health concern in Ireland?

PubMed

Canty, Mary J; Fogarty, Ursula; Sheridan, Michael K; Ensley, Steve M; Schrunk, Dwayne E; More, Simon J

2014-01-01

Four primary mycotoxicosis have been reported in livestock caused by fungal infections of grasses or cereals by members of the Clavicipitaceae family. Ergotism (generally associated with grasses, rye, triticale and other grains) and fescue toxicosis (associated with tall fescue grass, Festuca arundinacea) are both caused by ergot alkaloids, and referred to as 'ergot alkaloid intoxication'. Ryegrass staggers (associated with perennial ryegrass Lolium perenne) is due to intoxication with an indole-diperpene, Lolitrem B, and metabolites. Fescue-associated oedema, recently described in Australia, may be associated with a pyrrolizidine alkaloid, N-acetyl norloline. Ergotism, caused by the fungus Claviceps purpurea, is visible and infects the outside of the plant seed. Fescue toxicosis and ryegrass staggers are caused by Neotyphodium coenophalium and N. lolii, respectively. Fescue-associated oedema has been associated with tall fescue varieties infected with a specific strain of N. coenophialum (AR542, Max P or Max Q). The name Neotyphodium refers to asexual derivatives of Epichloë spp., which have collectively been termed the epichloë fungi. These fungi exist symbiotically within the grass and are invisible to the naked eye. The primary toxicological effect of ergot alkaloid involves vasoconstriction and/or hypoprolactinaemia. Ingestion of ergot alkaloid by livestock can cause a range of effects, including poor weight gain, reduced fertility, hyperthermia, convulsions, gangrene of the extremities, and death. To date there are no published reports, either internationally or nationally, reporting ergot alkaloid intoxication specifically associated with perennial ryegrass endophytes. However, unpublished reports from the Irish Equine Centre have identified a potential emerging problem of ergot alkaloid intoxication with respect to equines and bovines, on primarily perennial ryegrass-based diets. Ergovaline has been isolated in varying concentrations in the herbage of a

Ergot alkaloid intoxication in perennial ryegrass (Lolium perenne): an emerging animal health concern in Ireland?

PubMed Central

2014-01-01

Four primary mycotoxicosis have been reported in livestock caused by fungal infections of grasses or cereals by members of the Clavicipitaceae family. Ergotism (generally associated with grasses, rye, triticale and other grains) and fescue toxicosis (associated with tall fescue grass, Festuca arundinacea) are both caused by ergot alkaloids, and referred to as ‘ergot alkaloid intoxication’. Ryegrass staggers (associated with perennial ryegrass Lolium perenne) is due to intoxication with an indole-diperpene, Lolitrem B, and metabolites. Fescue-associated oedema, recently described in Australia, may be associated with a pyrrolizidine alkaloid, N-acetyl norloline. Ergotism, caused by the fungus Claviceps purpurea, is visible and infects the outside of the plant seed. Fescue toxicosis and ryegrass staggers are caused by Neotyphodium coenophalium and N. lolii, respectively. Fescue-associated oedema has been associated with tall fescue varieties infected with a specific strain of N. coenophialum (AR542, Max P or Max Q). The name Neotyphodium refers to asexual derivatives of Epichloë spp., which have collectively been termed the epichloë fungi. These fungi exist symbiotically within the grass and are invisible to the naked eye. The primary toxicological effect of ergot alkaloid involves vasoconstriction and/or hypoprolactinaemia. Ingestion of ergot alkaloid by livestock can cause a range of effects, including poor weight gain, reduced fertility, hyperthermia, convulsions, gangrene of the extremities, and death. To date there are no published reports, either internationally or nationally, reporting ergot alkaloid intoxication specifically associated with perennial ryegrass endophytes. However, unpublished reports from the Irish Equine Centre have identified a potential emerging problem of ergot alkaloid intoxication with respect to equines and bovines, on primarily perennial ryegrass-based diets. Ergovaline has been isolated in varying concentrations in the herbage of

Study on the Alkaloids in Tibetan Medicine Aconitum pendulum Busch by HPLC–MSn Combined with Column Chromatography

PubMed Central

Wang, Beibei; Dong, Jie; Ji, Jiaojiao; Yuan, Jiang; Wang, Jiali; Wu, Jiarui; Tan, Peng; Liu, Yonggang

2016-01-01

A rapid, convenient and effective identification method of alkaloids was established and an attempt on isolating and analyzing the alkaloids in Aconitum pendulum Busch was conducted successfully. In this article, four high-content components including deoxyaconitine, benzoylaconine, aconine and neoline were isolated by using column chromatography. HPLC–MSn was employed to deduce the regulations of fragmentation of diterpenoid alkaloids which displayed a characteristic behavior of loss of CO(28u), CH3COOH(60u), CH3OH(32u), H2O(18u) and C6H5COOH(122u). Then, according to fragmentation regulation of mass spectrometry, 42 alkaloids were found in A. pendulum. Among them, 38 compounds were identified and 29 alkaloids were reported for the first time for this herb. Therefore, this means that HPLC–MSn combined with column chromatography could work as an effective and reliable tool for rapid identification of the chemical components of herbal medicine. PMID:26896350

The Actions of Piperidine Alkaloids at Fetal Muscle-Type and Autonomic-Type Nicotinic Acetylcholine Receptors

USDA-ARS?s Scientific Manuscript database

Piperidine alkaloids are found in many species of plants including Conium maculatum, Nicotiana spp., and Lupinus spp. A pharmacodynamic comparison was made of the alkaloids ammodendrine, anabasine, anabaseine, and coniine in; SH-SY5Y cells which express autonomic-type nicotinic acetylcholine recept...

Fire ant alarm pheromone and venom alkaloids act in concert to attract parasitic phorid flies, Pseudacteon spp.

PubMed

Sharma, Kavita R; Fadamiro, Henry Y

2013-11-01

Pseudacteon tricuspis, Pseudacteon obtusus and Pseudacteon curvatus are three species of parasitic phorid flies (Diptera: Phoridae), which have been introduced as classical biological control agents of imported, Solenopsis fire ants (Hymenoptera: Formicidae) in the southern USA. Previous studies demonstrated the behavioral response of P. tricuspis to the venom alkaloids and alarm pheromone of the fire ant, S. invicta. In the present study, we compared the responses of P. tricuspis, P. obtusus and P. curvatus to Solenopsis invicta alarm pheromone, venom alkaloids, or a mixture of both chemicals in four-choice olfactometer bioassays. The main hypothesis tested was that the fire ant alarm pheromone and venom alkaloids act in concert to attract Pseudacteon phorid flies. Both sexes of all three Pseudacteon species were attracted to low doses of the fire ant alarm pheromone or venom alkaloids (i.e. 1 ant worker equivalent) alone. However, the flies were significantly more attracted to a mixture of both chemicals (i.e., 1:1 mixture of alarm pheromone+alkaloids) than to either chemical. The results suggest an additive rather than a synergistic effect of combining both chemicals. Comparing the fly species, P. tricuspis showed relatively greater attraction to cis alkaloids, whereas the alkaloid mixture (cis+trans) was preferred by P. obtusus and P. curvatus. In general, no key sexual differences were recorded, although females of P. tricuspis and P. obtusus showed slightly higher response than conspecific males to lower doses of the alarm pheromone. The ecological significance of these findings is discussed, and a host location model is proposed for parasitic phorid flies involving the use of fire ant alarm pheromone and venom alkaloids as long range and short range attractants, respectively. Published by Elsevier Ltd.

Establishment of a search library about benzylisoquinoline alkaloids based on selective separation on the binaphthyl column and standard analysis on C18 column.

PubMed

Liu, Qiaoxia; Zhou, Binbin; Wang, Xinliang; Ke, Yanxiong; Jin, Yu; Yin, Lihui; Liang, Xinmiao

2012-12-01

A search library about benzylisoquinoline alkaloids was established based on preparation of alkaloid fractions from Rhizoma coptidis, Cortex phellodendri, and Rhizoma corydalis. In this work, two alkaloid fractions from each herbal medicine were first prepared based on selective separation on the "click" binaphthyl column. And then these alkaloid fractions were analyzed on C18 column by liquid chromatography coupled with tandem mass spectrometry. Many structure-related compounds were included in these alkaloids fractions, which led to easy separation and good MS response in further work. Therefore, a search library of 52 benzylisoquinoline alkaloids was established, which included eight aporphine, 19 tetrahydroprotoberberine, two protopine, two benzyltetrahydroisoquinoline, and 21 protoberberine alkaloids. The information of the search library contained compound names, structures, retention times, accurate masses, fragmentation pathways of benzylisoquionline alkaloids, and their sources from three herbal medicines. Using such a library, the alkaloids, especially those trace and unknown components in some herbal medicine could be accurately and quickly identified. In addition, the distribution of benzylisoquinoline alkaloids in the herbal medicines could be also summarized by searching the source samples in the library. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sensing properties of pristine boron nitride nanostructures towards alkaloids: A first principles dispersion corrected study

NASA Astrophysics Data System (ADS)

Roondhe, Basant; Dabhi, Shweta D.; Jha, Prafulla K.

2018-05-01

To understand the underlying physics behind the interaction of biomolecules with the nanomaterials to use them practically as bio-nanomaterials is very crucial. A first principles calculation under the frame work of density functional theory is executed to investigate the electronic structures and binding properties of alkaloids (Caffeine and Nicotine) over single walled boron nitride nanotube (BNNT) and boron nitride nanoribbon (BNNR) to determine their suitability towards filtration or sensing of these molecules. We have also used GGA-PBE scheme with the inclusion of Van der Waals (vdW) interaction based on DFT-D2. Increase in the accuracy by incorporating the dispersion correction in the calculation is observed for the long range Van der Waals interaction. Binding energy range of BNNT and BNNR with both alkaloids have been found to be -0.35 to -0.76 eV and -0.45 to -0.91 eV respectively which together with the binding distance shows physisorption binding of these molecules to the both nanostructures. The transfer of charge between the BN nanostructures and the adsorbed molecule has also been analysed by using Lowdin charge analysis. The sensitivity of both nanostructures BNNT and BNNR towards both alkaloids is observed through electronic structure calculations, density of states and quantum conductance. The binding of both alkaloids with BNNR is stronger. The analysis of the calculated properties suggests absence of covalent interaction between the considered species (BNNT/BNNR) and alkaloids. The study may be useful in designing the boron nitride nanostructure based sensing device for alkaloids.

Alkaloid profiling of the traditional Chinese medicine Rhizoma corydalis using high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry

PubMed Central

Sun, Mingqian; Liu, Jianxun; Lin, Chengren; Miao, Lan; Lin, Li

2014-01-01

Since alkaloids are the major active constituents of Rhizoma corydalis (RC), a convenient and accurate analytical method is needed for their identification and characterization. Here we report a method to profile the alkaloids in RC based on liquid chromatography-tandem quadrupole time-of-flight mass spectrometry (LC–Q-TOF-MS/MS). A total of 16 alkaloids belonging to four different classes were identified by comparison with authentic standards. The fragmentation pathway of each class of alkaloid was clarified and their differences were elucidated. Furthermore, based on an analysis of fragmentation pathways and alkaloid profiling, a rapid and accurate method for the identification of unknown alkaloids in RC is proposed. The method could also be useful for the quality control of RC. PMID:26579385

Comparative study of fourteen alkaloids from Uncaria rhynchophylla hooks and leaves using HPLC-diode array detection-atmospheric pressure chemical ionization/MS method.

PubMed

Qu, Jialin; Gong, Tianxing; Ma, Bin; Zhang, Lin; Kano, Yoshihiro; Yuan, Dan

2012-01-01

The purpose of the study is to compare alkaloid profile of Uncaria rhynchophylla hooks and leaves. Ten oxindole alkaloids and four glycosidic indole alkaloids were identified using HPLC-diode array detection (DAD) or LC-atmospheric pressure chemical ionization (APCI)-MS method, and a HPLC-UV method for simultaneous quantification of major alkaloids was validated. The hooks are characterized by high levels of four oxindole alkaloids rhynchophylline (R), isorhynchophylline (IR), corynoxeine (C) and isocorynoxeine (IC), while the leaves contained high level of two glycosidic indole alkaloids vincoside lactam (VL) and strictosidine (S). The presented methods have proven its usefulness in chemical characterization of U. rhynchophylla hooks and leaves.

Two-step iron(0)-mediated N-demethylation of N-methyl alkaloids.

PubMed

Kok, Gaik B; Pye, Cory C; Singer, Robert D; Scammells, Peter J

2010-07-16

A mild and simple two-step Fe(0)-mediated N-demethylation of a number of tertiary N-methyl alkaloids is described. The tertiary N-methylamine is first oxidized to the corresponding N-oxide, which is isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provides the N-demethylated amine. Representative substrates include a number of opiate and tropane alkaloids. Key intermediates in the synthesis of semisynthetic 14-hydroxy pharmaceutical opiates such as oxycodone and oxymorphone are also readily N-demethylated using this method.

A new C20-diterpenoid alkaloid from Aconitum soongaricum var. pubescens.

PubMed

Chen, Lin; Shan, Lianhai; Xu, Wenliang; Zhang, Jifa; Huang, Shuai; Zhou, Xianli

2017-03-01

A new denudatine-type C 20 -diterpenoid alkaloid, pubesine (1), along with seven known diterpenoid alkaloids, altaconitine (2), 14-benzoylaconine (3), spicatine A (4), 14-benzoylaconine-8-palmitate (5), 14-O-acetylsenbusine A (6), senbusine A (7) and 14-acetylneoline (8) were isolated from the whole plant of Aconitum soongaricum var. pubescens. Their structures were elucidated by means of extensive spectroscopic analyses (NMR and HR-ESI-MS) and comparison with data reported in the literature. All compounds were evaluated for their cytotoxicity against H460, MCF-7 and Hep G2 human cancer cell lines.

Activities and Effects of Ergot Alkaloids on Livestock Physiology and Production

PubMed Central

Klotz, James L.

2015-01-01

Consumption of feedstuffs contaminated with ergot alkaloids has a broad impact on many different physiological mechanisms that alters the homeostasis of livestock. This change in homeostasis causes an increased sensitivity in livestock to perturbations in the ambient environment, resulting in an increased sensitivity to such stressors. This ultimately results in large financial losses in the form of production losses to livestock producers around the world. This review will focus on the underlying physiological mechanisms that are affected by ergot alkaloids that lead to decreases in livestock production. PMID:26226000

Staphylococcal enterotoxin A gene-carrying Staphylococcus aureus isolated from foods and its control by crude alkaloid from papaya leaves.

PubMed

Handayani, Lita; Faridah, Didah Nur; Kusumaningrum, Harsi D

2014-11-01

Staphylococcus aureus is a known pathogen causing intoxication by producing enterotoxins in food. Staphylococcal enterotoxin A is one of the enterotoxins commonly implicated in staphylococcal food poisoning. The ability of crude alkaloid extract from papaya leaves to inhibit the growth of S. aureus and staphylococcal enterotoxin A synthesis was investigated. Staphylococcal enterotoxin A gene-carrying S. aureus was isolated from raw milk and ready-to-eat foods. Crude alkaloid was extracted from ground, dried papaya leaves using ultrasonic-assisted extraction, and a MIC of the alkaloid was determined by the broth macrodilution method. Furthermore, S. aureus isolate was exposed to the crude alkaloid extract at one- and twofold MIC, and the expression of sea was subsequently analyzed using a quantitative reverse transcription real-time PCR. Ten isolates of S. aureus were obtained, and nine of those isolates were sea carriers. The yield of crude alkaloid extract was 0.48 to 1.82% per dry weight of papaya leaves. A MIC of crude alkaloid to S. aureus was 0.25 mg/ml. After exposure to the alkaloid at 0.25 and 0.5 mg/ml for 2 h, a significant increase in cycle threshold values of sea was observed. The sea was expressed 29 and 41 times less when S. aureus was exposed to crude alkaloid at one- and twofold MIC, respectively. This study revealed that crude alkaloid of papaya leaves could control staphylococcal enterotoxin A gene-carrying S. aureus by suppressing the expression of sea, in addition to the ability to inhibit the growth of S. aureus. The expression of sea was successfully quantified.

Complete inhibition of fetal movement in the day 40 pregnant goat model by the piperidine alkaloid anabasine but not related alkaloids

USDA-ARS?s Scientific Manuscript database

Four chemically similar alkaloids, anabasine, anabaseine, epibatidine and dimethylphenylpiperazinium (DMPP), are potent nicotinic acetylcholine receptor agonists of fetal muscle nicotinic acetylcholine receptors in human TE-671 cells. Based on results with these cells, we hypothesized that these alk...

Quercetin exerts synergetic anti-cancer activity with 10-hydroxy camptothecin.

PubMed

Tang, Qin; Ji, Fangling; Wang, Jingyun; Guo, Lianying; Li, Yachen; Bao, Yongming

2017-11-15

Quercetin (Qu) is known as a dietary antioxidant with numerous bioactivities, but its function in anti-cancer has not been fully investigated. Here, we show that Qu at low doses (≤10μM) significantly enhances the inhibition of 10-hydroxy camptothecin (HCPT) on the proliferation of MCF7, BGC823 and HepG2 cells. A plasmid DNA relaxation assay indicates that the inhibition of HCPT on the catalytic activity of topoisomerase I (Topo I) is increased by Qu at 10μM. Compared to the treatment by Qu or HCPT alone, phosphorylation at Ser 139 of γH2A.X in MCF7 cells starts to increase significantly (P<0.05) at 6h when treated by the combination of 10μM Qu and 0.62μM HCPT. Moreover, the combinational group successively arrests MCF7 cells at G1, S and G2/M phases from 12h to 48h via up-regulation of p21 and induces apoptosis at 24h by triggering intrinsic cell death pathways. In addition, the inhibition effects of the combinational group on the proliferation of MCF7 cells are eliminated by pretreatment with 100μM Z-VAD-FMK (a caspase inhibitor). Finally, by using nude mice xenografting assay of MCF7 cells, we demonstrate that tumor inhibition rates of combinational group are significantly higher than single-drug group. In summary, the synergic anti-cancer mechanism of Qu and HCPT in MCF7 cells is through the combined inhibitory effects of Qu and HCPT on Topo I, which synergistically induce cell cycle arrest and apoptosis by triggering DNA damage. Copyright © 2017. Published by Elsevier B.V.

Permeability of ergot alkaloids across the blood-brain barrier in vitro and influence on the barrier integrity

PubMed Central

Mulac, Dennis; Hüwel, Sabine; Galla, Hans-Joachim; Humpf, Hans-Ulrich

2012-01-01

Scope Ergot alkaloids are secondary metabolites of Claviceps spp. and they have been in the focus of research for many years. Experiments focusing on ergotamine as a former migraine drug referring to the ability to reach the brain revealed controversial results. The question to which extent ergot alkaloids are able to cross the blood-brain barrier is still not answered. Methods and results In order to answer this question we have studied the ability of ergot alkaloids to penetrate the blood-brain barrier in a well established in vitro model system using primary porcine brain endothelial cells. It could clearly be demonstrated that ergot alkaloids are able to cross the blood-brain barrier in high quantities in only a few hours. We could further identify an active transport for ergometrine as a substrate for the BCRP/ABCG2 transporter. Investigations concerning barrier integrity properties have identified ergocristinine as a potent substance to accumulate in these cells ultimately leading to a weakened barrier function. Conclusion For the first time we could show that the so far as biologically inactive described 8-(S) isomers of ergot alkaloids seem to have an influence on barrier integrity underlining the necessity for a risk assessment of ergot alkaloids in food and feed. PMID:22147614

Livestock Poisoning with Pyrrolizidine Alkaloid Containing Plants (Senecio, Crotalaria, Cynoglossum, Amsinckia, Heliotropium and Echium spp.)

USDA-ARS?s Scientific Manuscript database

Pyrrolizidine alkaloids (PAs) are potent liver toxins that have been identified in over 6,000 plants throughout the world. Alkaloids are nitrogen-based compounds with potent biological activity. About half of the identified PAs are toxic and several cause cancer (carcinogenic). PA-containing plants...

Cases of ergotism in livestock and associated ergot alkaloid concentrations in feed

NASA Astrophysics Data System (ADS)

Craig, A.; Klotz, James; Duringer, Jennifer

2015-02-01

Ergot-induced disease was known long before Biblical times and has been the root cause for countless human epidemics spanning from the early fourteenth century to the late sixteenth century. In contrast, many of these same ergot alkaloids have been utilized for their medicinal properties to mitigate migraine headaches and have had indications as anticarcinogens. Although ergot alkaloids have been used for centuries, basic pharmacokinetic data has not been documented for clinical disease. Consequently, a threshold dose and accurate dose-response data have yet to be established. Throughout the past several years, new detection techniques have emerged to detect these alkaloids at the parts per billion which have allowed for new efforts to be made with respect to determining threshold levels and making accurate clinical diagnoses. This perspectives article provides a critical initial step for establishing a uniform interpretation of ergot toxicosis from limited existing data.

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

A novel alkaloid isolated from Crotalaria paulina and identified by NMR and DFT calculations

NASA Astrophysics Data System (ADS)

Oliveira, Ramon Prata; Demuner, Antonio Jacinto; Alvarenga, Elson Santiago; Barbosa, Luiz Claudio Almeida; de Melo Silva, Thiago

2018-01-01

Pyrrolizidine alkaloids (PAs) are secondary metabolites found in Crotalaria genus and are known to have several biological activities. A novel macrocycle bislactone alkaloid, coined ethylcrotaline, was isolated and purified from the aerial parts of Crotalaria paulina. The novel macrocycle was identified with the aid of high resolution mass spectrometry and advanced nuclear magnetic resonance techniques. The relative stereochemistry of the alkaloid was defined by comparing the calculated quantum mechanical hydrogen and carbon chemical shifts of eight candidate structures with the experimental NMR data. The best fit between the eight candidate structures and the experimental NMR chemical shifts was defined by the DP4 statistical analyses and the Mean Absolute Error (MAE) calculations.

An old yellow enzyme gene controls the branch point between Aspergillus fumigatus and Claviceps purpurea ergot alkaloid pathways.

PubMed

Coyle, Christine M; Cheng, Johnathan Z; O'Connor, Sarah E; Panaccione, Daniel G

2010-06-01

Ergot fungi in the genus Claviceps and several related fungal groups in the family Clavicipitaceae produce toxic ergot alkaloids. These fungi produce a variety of ergot alkaloids, including clavines as well as lysergic acid derivatives. Ergot alkaloids are also produced by the distantly related, opportunistic human pathogen Aspergillus fumigatus. However, this fungus produces festuclavine and fumigaclavines A, B, and C, which collectively differ from clavines of clavicipitaceous fungi in saturation of the last assembled of four rings in the ergoline ring structure. The two lineages are hypothesized to share early steps of the ergot alkaloid pathway before diverging at some point after the synthesis of the tricyclic intermediate chanoclavine-I. Disruption of easA, a gene predicted to encode a flavin-dependent oxidoreductase of the old yellow enzyme class, in A. fumigatus led to accumulation of chanoclavine-I and chanoclavine-I-aldehyde. Complementation of the A. fumigatus easA mutant with a wild-type allele from the same fungus restored the wild-type profile of ergot alkaloids. These data demonstrate that the product of A. fumigatus easA is required for incorporation of chanoclavine-I-aldehyde into more-complex ergot alkaloids, presumably by reducing the double bond conjugated to the aldehyde group, thus facilitating ring closure. Augmentation of the A. fumigatus easA mutant with a homologue of easA from Claviceps purpurea resulted in accumulation of ergot alkaloids typical of clavicipitaceous fungi (agroclavine, setoclavine, and its diastereoisomer isosetoclavine). These data indicate that functional differences in the easA-encoded old yellow enzymes of A. fumigatus and C. purpurea result in divergence of their respective ergot alkaloid pathways.

An Old Yellow Enzyme Gene Controls the Branch Point between Aspergillus fumigatus and Claviceps purpurea Ergot Alkaloid Pathways▿

PubMed Central

Coyle, Christine M.; Cheng, Johnathan Z.; O'Connor, Sarah E.; Panaccione, Daniel G.

2010-01-01

Ergot fungi in the genus Claviceps and several related fungal groups in the family Clavicipitaceae produce toxic ergot alkaloids. These fungi produce a variety of ergot alkaloids, including clavines as well as lysergic acid derivatives. Ergot alkaloids are also produced by the distantly related, opportunistic human pathogen Aspergillus fumigatus. However, this fungus produces festuclavine and fumigaclavines A, B, and C, which collectively differ from clavines of clavicipitaceous fungi in saturation of the last assembled of four rings in the ergoline ring structure. The two lineages are hypothesized to share early steps of the ergot alkaloid pathway before diverging at some point after the synthesis of the tricyclic intermediate chanoclavine-I. Disruption of easA, a gene predicted to encode a flavin-dependent oxidoreductase of the old yellow enzyme class, in A. fumigatus led to accumulation of chanoclavine-I and chanoclavine-I-aldehyde. Complementation of the A. fumigatus easA mutant with a wild-type allele from the same fungus restored the wild-type profile of ergot alkaloids. These data demonstrate that the product of A. fumigatus easA is required for incorporation of chanoclavine-I-aldehyde into more-complex ergot alkaloids, presumably by reducing the double bond conjugated to the aldehyde group, thus facilitating ring closure. Augmentation of the A. fumigatus easA mutant with a homologue of easA from Claviceps purpurea resulted in accumulation of ergot alkaloids typical of clavicipitaceous fungi (agroclavine, setoclavine, and its diastereoisomer isosetoclavine). These data indicate that functional differences in the easA-encoded old yellow enzymes of A. fumigatus and C. purpurea result in divergence of their respective ergot alkaloid pathways. PMID:20435769