Science.gov

Sample records for naphthoquinones

  1. Tubulin-perturbing naphthoquinone spiroketals.

    PubMed

    Balachandran, Raghavan; Hopkins, Tamara D; Thomas, Catherine A; Wipf, Peter; Day, Billy W

    2008-02-01

    Several natural and synthetic naphthoquinone spiroketals are potent inhibitors of the thioredoxin-thioredoxin reductase redox system. Based on the antimitotic and weak antitubulin actions noted for SR-7 ([8-(furan-3-ylmethoxy)-1-oxo-1,4-dihydronaphthalene-4-spiro-2'-naphtho[1'',8''-de][1',3'][dioxin]), a library of related compounds was screened for tubulin-perturbing properties. Two compounds, TH-169 (5'-hydroxy-4'H-spiro[1,3-dioxolane-2,1'-naphthalen]-4'-one) and TH-223 (5'-methoxy-4'H-spiro[1,3-dioxane-2,1'-naphthalen]-4'-one), had substantial effects on tubulin assembly and were antiproliferative at low micromolar concentrations. TH-169 was the most potent at blocking GTP-dependent polymerization of 10 mum tubulin in vitro with a remarkable 50% inhibitory concentration of ca. 400 nm. It had no effect on paclitaxel-induced microtubule assembly and did not cause microtubule hypernucleation. TH-169 failed to compete with colchicine for binding to beta-tubulin. The 50% antiproliferative concentration of TH-169 against human cancer cells was at or slightly below 1 mum. Flow cytometry showed that 1 mum TH-169 caused an increase in G(2)/M and hypodiploid cells. TH-169 eliminated the PC-3 cells' polyploid population and increased their expression of p21(WAF1) and Hsp70 in a concentration-dependent manner. The antiproliferative effect of TH-169 was irreversible and independent of changes in caspases, actin, tubulin, glyceraldehyde phosphate dehydrogenase or Bcl-x(S/L). This structurally simple naphthoquinone spiroketal represents a small molecule, tubulin-interactive agent with a novel apoptotic pathway and attractive biological function. PMID:18194192

  2. Luciferase inhibition by a novel naphthoquinone.

    PubMed

    Bedford, Rebecca; LePage, Daniel; Hoffmann, Rachel; Kennedy, Steven; Gutschenritter, Tyler; Bull, Lauren; Sujijantarat, Nanthiya; DiCesare, John C; Sheaff, Robert J

    2012-02-01

    The novel naphthoquinone 12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was created as a potential chemotherapeutic agent. Previous work showed it is an irreversible inhibitor of type I and II topoisomerases that alkylates specific enzyme thiols. While analyzing the effect of TU100 on cancer cells, we discovered it is a potent inhibitor of luciferase derived from both Photinus pyralis (fireflies) and Renilla reniformis (sea pansy). Pre-incubation experiments showed that TU100 does not irreversibly inactivate luciferase, indicating its mechanism is different from that observed with topoisomerases. Firefly luciferase generates light using ATP and luciferin as substrates (bioluminescence). An examination of TU100 inhibition at varying substrate concentrations revealed the drug is uncompetitive with respect to ATP and competitive with respect to luciferin. The TU100 binding constant (K(I)) is 2.5±0.7 μM as determined by Dixon plot analysis. These data suggest TU100 specifically binds the luciferase-ATP complex and prevents its interaction with luciferin. Given the novel structure of TU100, unique mechanism of action, and ability to target luciferase from different species, these results identify TU100 as an important new reagent for investigating and regulating bioluminescent enzymes.

  3. Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors.

    PubMed

    Vafai, Scott B; Mevers, Emily; Higgins, Kathleen W; Fomina, Yevgenia; Zhang, Jianming; Mandinova, Anna; Newman, David; Shaw, Stanley Y; Clardy, Jon; Mootha, Vamsi K

    2016-01-01

    Deficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referred to as "complex I bypass." In the present study, we created a cellular model of complex I deficiency by using CRISPR genome editing to knock out Ndufa9 in mouse myoblasts, and utilized this cell line to develop a high-throughput screening platform for novel complex I bypass factors. We screened a library of ~40,000 natural product extracts and performed bioassay-guided fractionation on a subset of the top scoring hits. We isolated four plant-derived 1,4-naphthoquinone complex I bypass factors with structural similarity to menadione: chimaphilin and 3-chloro-chimaphilin from Chimaphila umbellata and dehydro-α-lapachone and dehydroiso-α-lapachone from Stereospermum euphoroides. We also tested a small number of structurally related naphthoquinones from commercial sources and identified two additional compounds with complex I bypass activity: 2-methoxy-1,4-naphthoquinone and 2-methoxy-3-methyl-1,4,-naphthoquinone. The six novel complex I bypass factors reported here expand this class of molecules and will be useful as tool compounds for investigating complex I disease biology. PMID:27622560

  4. Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors

    PubMed Central

    Mevers, Emily; Higgins, Kathleen W.; Fomina, Yevgenia; Zhang, Jianming; Mandinova, Anna; Newman, David; Shaw, Stanley Y.; Clardy, Jon; Mootha, Vamsi K.

    2016-01-01

    Deficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referred to as “complex I bypass.” In the present study, we created a cellular model of complex I deficiency by using CRISPR genome editing to knock out Ndufa9 in mouse myoblasts, and utilized this cell line to develop a high-throughput screening platform for novel complex I bypass factors. We screened a library of ~40,000 natural product extracts and performed bioassay-guided fractionation on a subset of the top scoring hits. We isolated four plant-derived 1,4-naphthoquinone complex I bypass factors with structural similarity to menadione: chimaphilin and 3-chloro-chimaphilin from Chimaphila umbellata and dehydro-α-lapachone and dehydroiso-α-lapachone from Stereospermum euphoroides. We also tested a small number of structurally related naphthoquinones from commercial sources and identified two additional compounds with complex I bypass activity: 2-methoxy-1,4-naphthoquinone and 2-methoxy-3-methyl-1,4,-naphthoquinone. The six novel complex I bypass factors reported here expand this class of molecules and will be useful as tool compounds for investigating complex I disease biology. PMID:27622560

  5. STABILITY OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF NAPHTHALENE OXIDE, 1,2-NAPHTHOQUINONE, AND 1,4-NAPHTHOQUINONE

    EPA Science Inventory

    Naphthalene is an important industrial chemical, which has recently been shown to cause tumors of the respiratory tract in rodents. It is thought that one or more reactive metabolites of naphthalene, namely, naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ), and 1,4-na...

  6. Further evidence that naphthoquinone inhibits Toxoplasma gondii growth in vitro.

    PubMed

    da Silva, Luciana Lemos Rangel; Portes, Juliana de Araujo; de Araújo, Marlon Heggdorne; Silva, Jéssica Lays Sant'ana; Rennó, Magdalena Nascimento; Netto, Chaquip Daher; da Silva, Alcides José Monteiro; Costa, Paulo Roberto Ribeiro; De Souza, Wanderley; Seabra, Sergio Henrique; DaMatta, Renato Augusto

    2015-12-01

    Toxoplasmosis is a widely disseminated disease caused by Toxoplasma gondii, an intracellular protozoan parasite. Standard treatment causes many side effects, such as depletion of bone marrow cells, skin rashes and gastrointestinal implications. Therefore, it is necessary to find chemotherapeutic alternatives for the treatment of this disease. It was shown that a naphthoquinone derivative compound is active against T. gondii, RH strain, with an IC50 around 2.5 μM. Here, three different naphthoquinone derivative compounds with activity against leukemia cells and breast carcinoma cell were tested against T. gondii (RH strain) infected LLC-MK2 cell line. All the compounds were able to inhibit parasite growth in vitro, but one of them showed an IC50 activity below 1 μM after 48 h of treatment. The compounds showed low toxicity to the host cell. In addition, these compounds were able to induce tachyzoite-bradyzoite conversion confirmed by morphological changes, Dolichus biflorus lectin cyst wall labeling and characterization of amylopectin granules in the parasites by electron microscopy analysis using the Thierry technique. Furthermore, the compounds induced alterations on the ultrastructure of the parasite. Taken together, our results point to the naphthoquinone derivative (LQB 151) as a potential compound for the development of new drugs for the treatment of toxoplasmosis. PMID:26335616

  7. 5'-monohydroxyphylloquinone is the dominant naphthoquinone of PSI in the green alga Chlamydomonas reinhardtii.

    PubMed

    Ozawa, Shin-ichiro; Kosugi, Makiko; Kashino, Yasuhiro; Sugimura, Takashi; Takahashi, Yuichiro

    2012-01-01

    Thylakoid membranes contain two types of quinones, benzoquinone (plastoquinone) and naphthoquinone, which are involved in photosynthetic electron transfer. Unlike the benzoquinone, the chemical species of naphthoquinone present (phylloquinone, menaquinone-4 and 5'-monohydroxyphylloquinone) varies depending on the oxygenic photosynthetic organisms. The green alga Chlamydomonas reinhardtii has been used as a model organism to study the function of the naphthoquinone bound to PSI. However, the level of phylloquinone and the presence of other naphthoquinones in this organism remain unknown. In the present study, we found that 5'-monohydroxyphylloquinone is the predominant naphthoquinone in cell and thylakoid extracts based on the retention time during reverse phase HPLC, absorption and mass spectrometry measurements. It was shown that 5'-monohydroxyphylloquinone is enriched 2.5-fold in the PSI complex as compared with thylakoid membranes but that it is absent from PSI-deficient mutant cells. We also found a small amount of phylloquinone in the cells and in the PSI complex and estimated that accumulated 5'-monohydroxyphylloquinone and phylloquinone account for approximately 90 and 10%, respectively, of the total naphthoquinone content. The ratio of these two naphthoquinones remained nearly constant in the cells and in the PSI complexes from logarithmic and stationary cell growth stages. We conclude that both 5'-monohydroxyphylloquinone and phylloquinone stably co-exist as major and minor naphthoquinones in Chlamydomonas PSI.

  8. Antimutagenic and antioxidant properties of plumbagin and other naphthoquinones.

    PubMed

    Kumar, Sanjeev; Gautam, Satyendra; Sharma, Arun

    2013-07-01

    The structure-function relationships of the naphthoquinone phytochemicals, plumbagin, juglone, and menadione, have been studied with regard to antimutagenic and antioxidant activities. Antimutagenicity of these compounds was assessed by the Ames test and RNA polymerase B (rpoB)-based rifampicin resistance assay. Antioxidant potential was evaluated by radical scavenging assays and reducing power measurement. Protection of cells and DNA against gamma radiation-induced oxidative damage was assayed by survival analysis and gel electrophoresis profiling, respectively. On the 1,4-naphthoquinone nucleus, plumbagin possesses 5-hydroxyl and 2-methyl functional groups, whereas juglone has only the 5-hydroxyl and menadione only the 2-methyl group. Plumbagin showed strong antimutagenic (against ultraviolet and ethyl methanesulfonate) and antioxidant activities, whereas juglone displayed only strong antimutagenic, and menadione only strong antioxidant activities. Thus, these two functional groups (5-OH/2-CH3) play important roles in the differential bioactivity of naphthoquinones. Escherichia coli, microarray analysis showed upregulation of the genes rep (replication/repair), ybaK (tRNA editing), speE (spermidine synthesis), and yjfC (glutathionyl spermidine synthesis) by plumbagin or juglone, and sodC (superoxide dismutase), xthA (oxidative repair), hycB (electron carrier between hydrogenase 3 and fumarate dehydrogenase), and ligA (formation of phosphodiester bond in DNA) by plumbagin or menadione. Studies with E. coli single-gene knockouts showed that ybaK and speE, reported to prevent mistranslation, are likely to be involved in the antimutagenicity displayed by juglone, and sodC to be involved in the antioxidant activity of menadione.

  9. A new and efficient procedure for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones

    PubMed Central

    Reis, Marcelo Isidoro P; Campos, Vinícius R; Resende, Jackson A L C; Silva, Fernando C

    2015-01-01

    Summary A new and efficient method for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones in one step with high yields from the reaction of lawsone with 1,3,5-triazinanes was developed. PMID:26425181

  10. MEASUREMENT OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF NAPHTHALENE-1,2-OXIDE, 1,2-NAPHTHOQUINONE AND 1,4-NAPHTHOQUINONE AFTER ADMINISTRATION OF NAPHTHALENE TO F344 RATS

    EPA Science Inventory

    Naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) are the major metabolites of naphthalene that are thought to be responsible for the cytotoxicity and genotoxicity of this chemical. We measured cysteinyl adducts of these metabolites in ...

  11. Synthesis and biological evaluation of novel ferrocene-naphthoquinones as antiplasmodial agents.

    PubMed

    García-Barrantes, Pedro M; Lamoureux, Guy V; Pérez, Alice L; García-Sánchez, Rory N; Martínez, Antonio R; San Feliciano, Arturo

    2013-01-01

    This work deals with the synthesis and evaluation of new compounds designed by combination of 1,4-naphthoquinone and ferrocene fragments in a 3-ferrocenylmethyl-2-hydroxy-1,4-naphthoquinone arrangement. A practical coupling reaction between 2-hydroxy-1,4-naphthoquinone and ferrocenemethanol derivatives has been developed. This procedure can be carried out "on-water", at moderate temperatures and without auxiliaries or catalysts, with moderate to high yields. The synthesized derivatives have shown significant in vitro antiplasmodial activity against chloroquine-sensitive and resistant Plasmodium falciparum strains and it has been shown that this activity is not related to the inhibition of biomineralization of ferriprotoporphyrin IX. Binding energy calculations and docking of these compounds to cytochrome b in comparison with atovaquone have been performed.

  12. Spectral and structural characterization of 2-(fluorophenylamino)- and 2-(nitrophenylamino)-1,4-naphthoquinone derivatives

    NASA Astrophysics Data System (ADS)

    Leyva, Elisa; Schmidtke Sobeck, Sarah J.; Loredo-Carrillo, Silvia E.; Magaldi-Lara, Diego A.

    2014-06-01

    Naphthoquinone amino derivatives exhibit interesting physicochemical properties and are of interest for potential medicinal purposes. The preparation of novel 2-(nitrophenylamino)-1,4-naphthoquinones derivatives was achieved by reaction of nitroanilines with 1,4-naphthoquinone with a catalytic amount of FeCl3 or by direct nitration of 2-(phenylamino)-1,4-naphthoquinone (PAN). Structural and photophysical properties of a series of NO2PANs and FPANs derivatives are examined using computational and spectroscopic methods. Absorbance and emission spectra are measured in a range of solvent environments to examine the impact of solvent-solute interactions. Additionally quantum calculations are used to evaluate the electronic nature of the spectral transitions and compare structures of the different PAN derivatives. The lowest energy electronic transitions have charge transfer character, and show the most sensitivity to solvent and substituents. Higher energy π-π* transitions are relatively insensitive to both factors. Computational predictions are in good agreement with the experimental spectra, and provide molecular-level insight variations amongst the different aniline-substituents.

  13. Extension of lifespan in C. elegans by naphthoquinones that act through stress hormesis mechanisms.

    PubMed

    Hunt, Piper R; Son, Tae Gen; Wilson, Mark A; Yu, Quian-Sheng; Wood, William H; Zhang, Yongqing; Becker, Kevin G; Greig, Nigel H; Mattson, Mark P; Camandola, Simonetta; Wolkow, Catherine A

    2011-01-01

    Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap'n'collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway.

  14. The Synthesis of 2-acetyl-1,4-naphthoquinone: A Multi-step Synthesis.

    ERIC Educational Resources Information Center

    Green, Ivan R.

    1982-01-01

    Outlines 2 procedures for synthesizing 2-acetyl-1,4-naphthoquinone to compare relative merits of the two pathways. The major objective of the exercise is to demonstrate that certain factors should be considered when selecting a pathway for synthesis including availability of starting materials, cost of reagents, number of steps involved,…

  15. Phytotoxic action of naphthoquinone juglone demonstrated on lettuce seedling roots.

    PubMed

    Babula, Petr; Vaverkova, Veronika; Poborilova, Zuzana; Ballova, Ludmila; Masarik, Michal; Provaznik, Ivo

    2014-11-01

    Juglone, 5-hydroxy-1,4-naphthoquinone, is the plant secondary metabolite with allelopathic properties, which was isolated especially from the plant species belonging to family Juglandaceae A. Rich. ex Kunth (walnut family). The mechanism of phytotoxic action of juglone was investigated on lettuce seedlings Lactuca sativa L. var. capitata L. cv. Merkurion by determining its effect at different levels. We have found that juglone inhibits mitosis (mitotic index 8.5 ± 0.6% for control versus 2.2 ± 0.9% for 250 μM juglone), changes mitotic phase index with accumulation of the cells in prophase (56.5 ± 2.6% for control versus 85.3 ± 5.0% for 250 μM juglone), and decreases meristematic activity in lettuce root tips (51.07 ± 3.62% for control versus 5.27 ± 2.29% for 250 μM juglone). In addition, juglone induced creation of reactive oxygen species and changed levels of reactive nitrogen species. Amount of malondialdehyde, a product of lipid peroxidation, increased from 24.0 ± 4.0 ng g(-1) FW for control to 55.5 ± 5.4 ng g(-1) FW for 250 μM juglone. We observed also changes in cellular structure, especially changes in the morphology of endoplasmic reticulum. Reactive oxygen species induced damage of plasma membrane. All these changes resulted in the disruption of the mitochondrial membrane potential, increase in free intracellular calcium ions, and DNA fragmentation and programmed cell death that was revealed by two methods, TUNEL test and DNA electrophoresis. The portion of TUNEL-positive cells increase from 0.96 ± 0.5% for control to 7.66 ± 1.5% for 250 μM juglone. Results of the study indicate complex mechanism of phytotoxic effect of juglone in lettuce root tips and may indicate mechanism of allelopathic activity of this compound. PMID:25240266

  16. Quantification of naphthoquinone mercapturic acids in urine as biomarkers of naphthalene exposure.

    PubMed

    Klotz, Katrin; Angerer, Jürgen

    2016-02-15

    Naphthalene shows carcinogenic properties in animal experiments. As the substance is ubiquitary present in the environment and has a possibly high exposure at industrial workplaces, the determination of naphthalene metabolites in humans is of environmental-medical as well as occupational-medical importance. Here, biomarkers of 1,2- and 1,4-naphthoquinone, as possibly carcinogenic metabolites in the naphthalene metabolism, are of outstanding significance. We developed and validated a liquid chromatography-tandem mass-spectrometric (LC-MS/MS) method for the simultaneous determination of the naphthoquinone mercapturic acids of 1,2- and 1,4-naphthoquinone in human urine samples as a sum of naphthoquinone- and dihydroxynaphthalene-mercapturic acid. Except for enzymatic hydrolysis and acidification, no further sample preparation is necessary. For sample clean-up, a column switching procedure is applied. The mercapturic acids are extracted from the urinary matrix on a restricted access material (RAM RP 18) and separated on a reversed phase column (Synergi Polar RP C18). The metabolites were quantified by tandem mass spectrometry using labelled D5-1,4-NQMA as internal standard. The limits of detection are 3μg/l for 1,2-NQMA and 1μg/l for 1,4-NQMA. Intraday- and interday precision for pooled urine (spiked with 10μg/l and 30μg/l of the analytes) ranges from 5.9 to 15.1% for 1,2-NQMA and from 2.0 to 10.8% for 1,4-NQMA. The developed method is suited for the sensitive and specific determination of the mercapturic acids of naphthoquinones in human urine. A good precision and low limits of detection were achieved. Application of those new biomarkers in biomonitoring studies may give deeper insights into the mechanisms of the human naphthalene metabolism. PMID:26812176

  17. [Allosteric regulation of glucosamine synthetase activity by naphthoquinone derivatives and ethyl ester of di-(4-oxycumarinyl-3)-acetic acid].

    PubMed

    Sharaev, P N; Bogdanov, N G; Sarycheva, I K; Zhukova, E E

    1981-02-01

    The effects of derivatives of naphthoquinone, e.g. 2-methyl-3-phytyl-1,4-naphthoquinone (vitamin K1), 2-methyl-1,4-naphthoquinone (vitamin K3), 3-dihydro-2-methyl-1,4-naphthoquinone-2-sodium sulfonate (vicasol), derivatives of naphthohydroxyquinone, e.g. 2-methyl-1,4-naphthohydroxyquinone 1-monoacetate, 2-methyl-1,4-naphthohydroxyquinone 1,4-diacetate and the oxycumarine derivative di-(4-oxycumarinyl-3)-acetate ethyl ester (pelentan) on the activity of purified glutamine synthetase (EC 5.3.1.19) from rat liver were studied. The enzyme activity was increased under effects of vitamins K1 and K3 and was inhibited by pelentan. The data obtained are indicative of the allosteric effect of these compounds on the enzyme. PMID:7195738

  18. A naphthoquinone/SAM-mediated biosensor for olive oil polyphenol content.

    PubMed

    Hammami, Asma; Kuliček, Jaroslav; Raouafi, Noureddine

    2016-10-15

    We report on the design of an amperometric tyrosinase-based biosensor using a self-assembled monolayer of ω-mercaptopropyl naphthoquinone on gold electrode as an electron mediator. Under optimal conditions (i.e. pH=7.4 and E=-0.35V vs. KCl), the chronoamperometric response of the naphthoquinone-modified bioelectrode to successive additions of phenol was evaluated. The biosensor exhibits sensitive bioelectrocatalytic response at a working potential of -0.35V vs. Ag/AgCl (sat.KCl), reaching the steady-state current within 40s after each addition of phenol solution with a range of 0-135μM and a limit of detection and quantification which are 0.019μM and 0.0633μM, respectively. The bioelectrode was used to determine the content in polyphenol in a local virgin olive oil. PMID:27173563

  19. Thiourea-catalyzed Diels–Alder reaction of a naphthoquinone monoketal dienophile

    PubMed Central

    Kramer, Carsten S

    2013-01-01

    Summary A variety of organocatalysts were screened for the catalysis of the naphthoquinone monoketal Diels–Alder reaction. In this study we found that Schreiner's thiourea catalyst 10 and Jacobson's thiourea catalyst 12 facilitate the cycloaddition of the sterically hindered naphthoquinone monoketal dienophile 3 with diene 4. The use of thiourea catalysis allowed for the first time the highly selective synthesis of the exo-product 2a in up to 63% yield. In this reaction a new quaternary center was built. The so formed cycloaddition product 2a represents the ABC tricycle of beticolin 0 (1) and is also a valuable model substrate for the total synthesis of related natural products. PMID:23946836

  20. A naphthoquinone/SAM-mediated biosensor for olive oil polyphenol content.

    PubMed

    Hammami, Asma; Kuliček, Jaroslav; Raouafi, Noureddine

    2016-10-15

    We report on the design of an amperometric tyrosinase-based biosensor using a self-assembled monolayer of ω-mercaptopropyl naphthoquinone on gold electrode as an electron mediator. Under optimal conditions (i.e. pH=7.4 and E=-0.35V vs. KCl), the chronoamperometric response of the naphthoquinone-modified bioelectrode to successive additions of phenol was evaluated. The biosensor exhibits sensitive bioelectrocatalytic response at a working potential of -0.35V vs. Ag/AgCl (sat.KCl), reaching the steady-state current within 40s after each addition of phenol solution with a range of 0-135μM and a limit of detection and quantification which are 0.019μM and 0.0633μM, respectively. The bioelectrode was used to determine the content in polyphenol in a local virgin olive oil.

  1. Polymorphism in chloro derivatives of 1,4-naphthoquinone: Experiment and density functional theoretic investigations

    NASA Astrophysics Data System (ADS)

    Chaudhari, Dinkar; Gejji, Shridhar P.; Lande, Dipali N.; Chakravarty, Debamitra; Salunke-Gawali, Sunita

    2016-09-01

    Molecular interactions underlying polymorphs of chlorine containing 1,4-naphthoquinone derivatives have been investigated by employing single crystal X-ray, 1H NMR, FTIR and electronic spectra experiments combined with density functional theory. Two polymorphs of 2,3-dichloro-1,4-naphthoquinone possessing (i) triclinic space group P-1(A1 and A3), and (ii) orthorhombic with Pb21a (A2) space group were obtained. The polymorph A3 has two molecules in its asymmetric unit which facilitate Csbnd H⋯O interactions engendeing polymeric planar sheets. The two polymorphs of 2-amino-3-chloro-1,4-naphthoquinone reveal monoclinic forms with Pc (B1) and C2/C (B2) space groups. A tetramer of B2 molecule possess Nsbnd H⋯O interactions. The polymorphs of 2-chloro-3-hydroxy-1,4-naphthoquinone crystallizes in monoclinic space groups Pc (C1) and Pn (C2). Polymeric chain of C2 molecules results via Osbnd H⋯O interactions and the chains further are connected through Csbnd H⋯Cl and π-π stacking interactions those arise from benzenoid and quinonoid centroid. Moreover A3 facilitates the dimer via the halogen bonding interactions. Furthermore hydrogen bonding renders stability to the dimer C2. On the other hand compound B2 does not favor dimer formation. These inferences based on experimental observations are rationalized through the use of the dispersion corrected M06-2x functional based density functional theory. Further time dependent density functional theory has been used to assign the electronic transitions in UV-visible spectra of A3, B2 and C2.

  2. Copper-catalyzed divergent oxidative pathways of 2-naphthol derivatives: ortho-naphthoquinones versus 2-BINOLs.

    PubMed

    Kim, H Y; Takizawa, S; Oh, K

    2016-07-26

    Catalyst-dependent divergent pathways of 2-naphthol derivatives have been investigated. A readily available CuCl2-DMAP catalyst system promotes the aerobic oxidation of 2-naphthol derivatives to ortho-naphthoquinones whereas switching the catalyst system to Cu(OAc)2-DBN under an argon atmosphere allows the oxidative coupling of 2-naphthols to 1,1'-bi-2-naphthols (BINOLs) in good to excellent yields. PMID:27404292

  3. Naphthoquinones as broad spectrum biocides for treatment of ship's ballast water: toxicity to phytoplankton and bacteria.

    PubMed

    Wright, D A; Dawson, R; Cutler, S J; Cutler, H G; Orano-Dawson, C E; Graneli, E

    2007-03-01

    Current UN International Maritime Organization legislation mandates the phased introduction of ballast water treatment technologies capable of complying with rigorous standards related to removal of waterborne organisms. Doubts concerning mechanical treatments at very high ballasting rates have renewed interest in chemical treatment for very large vessels. High removal rates for biota require broad spectrum biocides that are safe to transport and handle and pose no corrosion problems for ships' structure. The current study focuses on the naphthoquinone group of compounds and extends a previously reported set of screening bioassays with an investigation of the toxicity of four naphthoquinones to select protists and prokaryotes, representative of typical ballast water organisms. Vegetative dinoflagellate cysts exposed to 2.0 mg/L of the naphthoquinones juglone, plumbagin, menadione and naphthazarin showed varying degrees of chloroplast destruction, with menadione demonstrating the most potency. Laboratory and mesocosm exposures of various phytoplankton genera to menadione showed toxicity at 1.0 mg/L. Juglone demonstrated the most bactericidal activity as judged by a Deltatox assay (Vibrio fischeri) and by acridine orange counts of natural bacterial populations.

  4. Naphthoquinones and Bioactive Compounds from Tobacco as Modulators of Neuronal Nitric Oxide Synthase Activity

    PubMed Central

    Venkatakrishnan, Priya; Gairola, C. Gary; Castagnoli, Neal; Miller, R. Timothy

    2009-01-01

    Studies were conducted with extracts of several varieties of tobacco in search of neuronal nitric oxide synthase (nNOS) inhibitors which may be of value in the treatment of stroke. Current therapies do not directly exploit modulation of nNOS activity due to poor selectivity of the currently available nNOS inhibitors. The properties of a potentially novel nNOS inhibitor(s) derived from tobacco extracts, and the concentration-dependent, modulatory effects of the tobacco-derived naphthoquinone compound, 2, 3, 6-trimethyl-1, 4-naphthoquinone (TMN), on nNOS activity were investigated, using 2-methyl-1, 4-naphthoquinone (menadione) as a control. Up to 31μM, both TMN and menadione stimulated nNOS-catalyzed L-citrulline production. However, at higher concentrations of TMN (62.5-500 μM), the stimulation was lost in a concentration-dependent manner. With TMN, the loss of stimulation did not decrease beyond the control activity. With menadione (62.5-500 μM), the loss of stimulation surpassed that of the control (78 ± 0.01%), indicating a complete inhibition of nNOS activity. This study suggests that potential nNOS inhibitors are present in tobacco, most of which remain to be identified. PMID:19367663

  5. Synthesis and Biological Evaluation of 1,4-Naphthoquinones and Quinoline-5,8-diones as Antimalarial and Schistosomicidal Agents

    PubMed Central

    Lanfranchi, Don Antoine; Cesar-Rodo, Elena; Bertrand, Benoît; Huang, Hsin-Hung; Day, Latasha; Johann, Laure; Elhabiri, Mourad; Becker, Katja; Williams, David L.

    2012-01-01

    Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The AgII-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO3 and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of β-hematin. PMID:22777178

  6. Singlet oxygen production by pyrano and furano 1,4-naphthoquinones in non-aqueous medium.

    PubMed

    de Lucas, Nanci C; Corrêa, Rodrigo J; Garden, Simon J; Santos, Guilherme; Rodrigues, Reinaldo; Carvalho, Carlos Eduardo M; Ferreira, Sabrina B; Netto-Ferreira, José Carlos; Ferreira, Vitor F; Miro, Paula; Marin, M Luisa; Miranda, Miguel A

    2012-07-01

    The influence of ring size on the photobehaviour of condensed 1,4-naphthoquinone systems, such as pyrano- and furano-derivatives (1 and 2, respectively) has been investigated. The absorption spectra for both families of naphthoquinones reveal clear differences; in the case of 2 they extend to longer wavelengths. A solvatochromic red shift in polar solvents is consistent with the π,π* character of the S(0)→ S(1) electronic transition in all cases. Theoretical (B3LYP) analysis of the HOMO and LUMO Kohn-Sham molecular orbitals of the S(0) state indicates that they are π and π* in nature, consistent with the experimental observation. A systematic study on the efficiency of singlet oxygen generation by these 1,4-naphthoquinones is presented, and values larger than 0.7 were found in every case. In accordance with these results, laser flash photolysis of deoxygenated acetonitrile solutions led to the formation of detectable triplet transient species with absorptions at 390 and 450 nm (1) and at 370 nm (2), with φ(ISC) close to 1. Additionally, the calculated energies for the T(1) states relative to the S(0) states at UB3LYP/6-311++G** are ca. 47 kcal mol(-1) for 1 and 43 kcal mol(-1) for 2. A comparison of the geometrical parameters for the S(0) and T(1) states reveals a marked difference with respect to the arrangement of the exocyclic phenyl ring whilst a comparison of electronic parameters revealed the change from a quinone structure to a di-dehydroquinone diradical structure. PMID:22441459

  7. New lanostanes and naphthoquinones isolated from Antrodia salmonea and their antioxidative burst activity in human leukocytes.

    PubMed

    Shen, Chien-Chang; Shen, Yuh-Chiang; Wang, Yea-Hwey; Lin, Lie-Chwen; Don, Ming-Jaw; Liou, Kuo-Tong; Wang, Wen-Yen; Hou, Yu-Chang; Chang, Tun-Tschu

    2006-02-01

    Four new compounds were isolated from the basidiomata of the fungus Antrodia salmonea, a newly identified species of Antrodia (Aphyllophorales) in Taiwan. These new compounds are named as lanosta-8,24-diene-3beta,15alpha,21-triol (1), 24-methylenelanost-8-ene-3beta,15alpha,21-triol (2), 2,3-dimethoxy-5-(2',5'-dimethoxy-3',4'-methylenedioxyphenyl)-7-methyl-[1,4]-naphthoquinone (3), and 2,3-dimethoxy-6-(2',5'-dimethoxy-3',4'-methylenedioxyphenyl)-7-methyl-[1,4]-naphthoquinone (4), respectively. Their structures were elucidated by spectroscopic methods. An in vitro cellular functional assay was performed to evaluate their anti-oxidative burst activity in human leukocytes. They showed inhibitory effects against phorbol 12-myristate-13-acetate (PMA), a direct protein kinase C activator, induced oxidative burst in neutrophils (PMN) and mononuclear cells (MNC) with 50 % inhibitory concentration (IC(50)) ranging from 3.5 to 25.8 microM. The potency order of these compounds in PMA-activated leukocytes was as 1 > 3 > 4 > 2. They were relatively less effective in formyl-Met-Leu-Phe (fMLP), a G-protein coupled receptor agonist, induced oxidative burst, except for compounds 3 and 4 in fMLP-activated PMN. These results indicated that three (1, 3, and 4) of these four newly identified compounds displayed anti-oxidative effect in human leukocytes with different potency and might confer anti-inflammatory activity to these drugs.

  8. 1,4-Naphthoquinone and other nutrient requirements of Succinivibrio dextrinosolvens.

    PubMed

    Gomez-Alarcon, R A; O'Dowd, C; Leedle, J A; Bryant, M P

    1982-08-01

    Three strains of Succinivibrio dextrinosolvens isolated from the rumen of cattle or sheep under diverse conditions grew well in a minimal medium containing glucose, minerals, cysteine, methionine, leucine, serine, ammonia, 1,4-naphthoquinone, p-aminobenzoic acid, and bicarbonate-carbonic acid buffer, pH 6.7. When menadione or vitamin K5 was substituted for 1,4-naphthoquinone, the growth rate was somewhat depressed. Growth was poor with vitamin K1 and ammonia, further addition of the amino acids aspartic acid, arginine, histidine, and tryptophan was necessary for good growth of type strain 24, but the other two strains grew well only in media containing ammonia. Strains C18 and 22B produced urease and grew well when ammonia replaced urea. When urea replaced ammonia, strain 24 grew poorly and urease activity could not be detected. Strain 24 required no B-vitamins, but the other two strains were stimulated by p-aminobenzoic acid. The methionine requirement was not placed by vitamin B12, betaine, or homocysteine. Cysteine was replaced by sulfide in strain 24 but less well in the other two strains. Very poor growth was obtained when sulfate replaced cysteine. The half-saturation constant for ammonia during growth of S. dextrinosolvens is more than 500 microM, a much higher value than that of many rumen bacteria.

  9. Targeting of Helicobacter pylori thymidylate synthase ThyX by non-mitotoxic hydroxy-naphthoquinones.

    PubMed

    Skouloubris, Stéphane; Djaout, Kamel; Lamarre, Isabelle; Lambry, Jean-Christophe; Anger, Karine; Briffotaux, Julien; Liebl, Ursula; de Reuse, Hilde; Myllykallio, Hannu

    2015-06-01

    ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the functionally analogous human enzyme, thus providing means for selective inhibition of bacterial growth. To identify novel compounds with anti-bacterial activity against the human pathogenic bacterium Helicobacter pylori, based on our earlier biochemical and structural analyses, we designed a series of eighteen 2-hydroxy-1,4-naphthoquinones (2-OH-1,4-NQs) that target HpThyX. Our lead-like molecules markedly inhibited the NADPH oxidation and 2'-deoxythymidine-5'-monophosphate-forming activities of HpThyX enzyme in vitro, with inhibitory constants in the low nanomolar range. The identification of non-cytotoxic and non-mitotoxic 2-OH-1,4-NQ inhibitors permitted testing their in vivo efficacy in a mouse model for H. pylori infections. Despite the widely assumed toxicity of naphthoquinones (NQs), we identified tight-binding ThyX inhibitors that were tolerated in mice and can be associated with a modest effect in reducing the number of colonizing bacteria. Our results thus provide proof-of-concept that targeting ThyX enzymes is a highly feasible strategy for the development of therapies against H. pylori and a high number of other ThyX-dependent pathogenic bacteria. We also demonstrate that chemical reactivity of NQs does not prevent their exploitation as anti-microbial compounds, particularly when mitotoxicity screening is used to prioritize these compounds for further experimentation. PMID:26040760

  10. Iron chelators and free radical scavengers in naturally occurring polyhydroxylated 1,4-naphthoquinones.

    PubMed

    Lebedev, Alexander V; Ivanova, Marina V; Levitsky, Dmitri O

    2008-01-01

    The cardioprotective effect of polyhydroxylated 1,4-naphthoquinones on the experimental model of myocardial ischemia-reperfusion has been demonstrated previously. In this study, using different models, such as bulk organic phase, liposomes and sarcoplasmic reticulum (SR) vesicles, we have shown the ability of naturally occurring polyhydroxynaphthoquinones, echinochrome (Ech), spinochromes C, D and E (SpC, SpD and SpE) to inhibit free-radical oxidation induced by heme iron (hemin) or by free iron ions (in ferrous/ascorbate system). The polyhydroxy-1,4-naphthoquinones (PHNQs) were more effective in inhibiting the phosphatidyl choline liposome peroxidation induced by ferrous/ascorbate than that induced by hemin. The iron chelating ability of PHNQs was determined spectrophotometrically. Prevention of the ferrous/ascorbate-induced leakage of calcium by Ech was demonstrated in isolated SR vesicles from rabbit skeletal muscle. The PHNQs displayed high scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. We concluded that iron chelation predominates in the overall antioxidant potential of the polyhydroxynaphthoquinones. PMID:18274994

  11. Luminescence of 1,4-naphthoquinone and the vitamin K system in Shpolskii matrices at 4 K

    NASA Astrophysics Data System (ADS)

    Vo-Dinh, Tuan; Wild, Urs P.

    This work investigates the high-resolution phosphorescence spectra of 1,4-naphthoquinone and the vitamin K system in Shpolskii solvents at 4 K. The quasi-linear vibronic bands are discussed with regard to spectral assignments and polarization data. The effect of non-totally symmetric vibrations is also discussed.

  12. QSAR on antiproliferative naphthoquinones based on a conformation-independent approach.

    PubMed

    Duchowicz, Pablo R; Bennardi, Daniel O; Bacelo, Daniel E; Bonifazi, Evelyn L; Rios-Luci, Carla; Padrón, José M; Burton, Gerardo; Misico, Rosana I

    2014-04-22

    The antiproliferative activities of a series of 36 naphthoquinone derivatives were subjected to a Quantitative Structure-Activity Relationships (QSAR) study. For this purpose a panel of four human cancer cell lines was used, namely HBL-100 (breast), HeLa (cervix), SW-1573 (non-small cell lung) and WiDr (colon). A conformation-independent representation of the chemical structure was established in order to avoid leading with the scarce experimental information on X-ray crystal structure of the drug interaction. The 1179 theoretical descriptors derived with E-Dragon and Recon software were simultaneously analyzed through linear regression models based on the Replacement Method variable subset selection technique. The established models were validated and tested through the use of external test sets of compounds, the Leave-One-Out Cross Validation method, Y-Randomization and Applicability Domain analysis.

  13. Naphthoquinone spiroketals and organic extracts from the endophytic fungus Edenia gomezpompae as potential herbicides.

    PubMed

    Macías-Rubalcava, Martha L; Ruiz-Velasco Sobrino, M Emma; Meléndez-González, Claudio; Hernández-Ortega, Simón

    2014-04-23

    From the fermentation mycelium of the endophytic fungus Edenia gomezpompae were obtained several phytotoxic compounds including two new members of the naphthoquinone spiroketal family, namely, palmarumycin EG1 (1) and preussomerin EG4 (4). In addition, preussomerins EG1-EG3 (7-9) and palmarumycins CP19 (2), CP17 (3), and CP2 (6), as well as ergosta-4,6,8(14),22-tetraen-3-one (5), were obtained. Compounds 2, 3, and 5 are new to this species. The structures of palmarumycins CP19 (2) and CP17 (3) were unambiguously determined by X-ray analysis. The isolates and mycelium organic extracts from four morphological variants of E. gomezpompae caused significant inhibition of seed germination, root elongation, and seedling respiration of Amaranthus hypochondriacus, Solanum lycopersicum, and Echinochloa crus-galli. The treatments also affected respiration on intact mitochondria isolated from spinach.

  14. QSAR on antiproliferative naphthoquinones based on a conformation-independent approach.

    PubMed

    Duchowicz, Pablo R; Bennardi, Daniel O; Bacelo, Daniel E; Bonifazi, Evelyn L; Rios-Luci, Carla; Padrón, José M; Burton, Gerardo; Misico, Rosana I

    2014-04-22

    The antiproliferative activities of a series of 36 naphthoquinone derivatives were subjected to a Quantitative Structure-Activity Relationships (QSAR) study. For this purpose a panel of four human cancer cell lines was used, namely HBL-100 (breast), HeLa (cervix), SW-1573 (non-small cell lung) and WiDr (colon). A conformation-independent representation of the chemical structure was established in order to avoid leading with the scarce experimental information on X-ray crystal structure of the drug interaction. The 1179 theoretical descriptors derived with E-Dragon and Recon software were simultaneously analyzed through linear regression models based on the Replacement Method variable subset selection technique. The established models were validated and tested through the use of external test sets of compounds, the Leave-One-Out Cross Validation method, Y-Randomization and Applicability Domain analysis. PMID:24631897

  15. Naphthalene and Naphthoquinone: Distributions and Human Exposure in the Los Angeles Basin

    NASA Astrophysics Data System (ADS)

    Lu, R.; Wu, J.; Turco, R.; Winer, A. M.; Atkinson, R.; Paulson, S.; Arey, J.; Lurmann, F.

    2003-12-01

    Naphthalene is the simplest and most abundant of the polycyclic aromatic hydrocarbons (PAHs). Naphthalene is found primarily in the gas-phase and has been detected in both outdoor and indoor samples. Evaporation from naphthalene-containing products (including gasoline), and during refining operations, are important sources of naphthalene in air. Naphthalene is also emitted during the combustion of fossil fuels and wood, and is a component of vehicle exhaust. Exposure to high concentrations of naphthalene can damage or destroy red blood cells, causing hemolytic anemia. If inhaled over a long period of time, naphthalene may cause kidney and liver damage, skin allergy and dermatitis, cataracts and retinal damage, as well as attack the central nervous system. Naphthalene has been found to cause cancer as a result of inhalation in animal tests. Naphthoquinones are photooxidation products of naphthalene and the potential health effects of exposure to these quinones are a current focus of research. We are developing and applying models that can be used to assess human exposure to naphthalene and its photooxidation products in major air basins such as California South Coast Air Basin (SoCAB). The work utilizes the Surface Meteorology and Ozone Generation (SMOG) airshed model, and the REgional Human EXposure (REHEX) model, including an analysis of individual exposure. We will present and discuss simulations of basin-wide distributions of, and human exposures to, naphthalene and naphthoquinone, with emphasis on the uncertainties in these estimates of atmospheric concentrations and human exposure. Regional modeling of pollutant sources and exposures can lead to cost-effective and optimally health-protective emission control strategies.

  16. Naphthoquinone based Chemosensor 2-(2‧-aminoethylpyridine)-3-chloro-1,4-naphthoquinone: Detection of metal ions, X-ray -crystal structures and DFT studies

    NASA Astrophysics Data System (ADS)

    Patil, Amit; Ware, Anuja P.; Bhand, Sujit; Chakrovarty, Debamitra; Gonnade, Rajesh; Pingale, Subhash S.; Salunke-Gawali, Sunita

    2016-06-01

    Naphthoquinone based Chemosensor 2; 2-(2‧-aminoethylpyridine)-3-chloro-1,4-napthoquinone have been synthesized and characterized. Chemosensor 2 crystallizes in the orthorhombic space group Pbcn and shows extensive intramolecular as well as intermolecular hydrogen bonding interactions. Each molecule of Chemosensor 2 showed interaction with five neighboring molecules via C-H⋯N, N-H⋯N, C-H⋯Cl and C-H⋯O interactions. Slipped π-π stacking interaction was observed in adjacent quinonoid and benzenoid rings. Chemosensor abilities of Chemosensor 2 ligand have been evaluated with metal ions viz. Cu2+, Ni2+, Zn2+, Co2+, Fe3+, Mn2+, Cr3+, Hg2+, La3+ and Cd2+ in methanol, methanol-water mixture and in presence of mild base triethylamine. Stoichiometry of Chemosensor 2 with metal ions such as Cu2+, Ni2+, Zn2+and Co2+ ions was determined by Jobs method in methanol and were found as 1:1 for Cu2+and 2:1 for Ni2+, Zn2+ Co2+. The variation in the metal ligand ratio is observed in aqueous media for Cu2+. Chemosensor 2 can be used selectively for naked eye detection of Cu2+ ions. The association constant obtained in methanol shows the trend Cu2+>Ni2+>Co2+. Cu2+ and two (Ni-1 and Ni-2) Ni2+ complexes were synthesized. Ni-2 complex showed coordination of Chemosensor 2 ligands was through pyridine nitrogen's only. The Chemosensor 2 and its deprotonated forms in methanol, water and triethylamine were also studied by TD-DFT studies.

  17. Studies on Cytotoxic Activity against HepG-2 Cells of Naphthoquinones from Green Walnut Husks of Juglans mandshurica Maxim.

    PubMed

    Zhou, Yuanyuan; Yang, Bingyou; Jiang, Yanqiu; Liu, Zhaoxi; Liu, Yuxin; Wang, Xiaoli; Kuang, Haixue

    2015-08-26

    Twenty-seven naphthoquinones and their derivatives, including four new naphthalenyl glucosides and twenty-three known compounds, were isolated from green walnut husks, which came from Juglans mandshurica Maxim. The structures of four new naphthalenyl glucosides were elucidated based on extensive spectroscopic analyses. All of these compounds were evaluated for their cytotoxic activities against the growth of human cancer cells lines HepG-2 by MTT [3-(4,5-dimethylthiazo l-2-yl)-2,5 diphenyl tetrazolium bromide] assay. The results were shown that most naphthoquinones in an aglycone form exhibited better cytotoxicity in vitro than naphthalenyl glucosides with IC50 values in the range of 7.33-88.23 μM. Meanwhile, preliminary structure-activity relationships for these compounds were discussed.

  18. Biarylmethane and Fused Heterocyclic Arene Synthesis via in Situ Generated o- and/or p-Naphthoquinone Methides.

    PubMed

    Sawama, Yoshinari; Kawajiri, Takahiro; Asai, Shota; Yasukawa, Naoki; Shishido, Yuko; Monguchi, Yasunari; Sajiki, Hironao

    2015-06-01

    o- and/or p-naphthoquinone methides (NQMs) can be selectively prepared by the ring opening of 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene derivatives based on a substituent effect at the 4 position of the substrates. The 4-alkyl- or silyl-substituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene was transformed to o-NQM (1-naphthoquinone-2-methide), which underwent Friedel-Crafts 1,4-addition of the α,β-unsaturated carbonyl moiety to provide the 2-benzyl-1-naphthol as the biarylmethane and [4 + 2]-cycloaddition with a dienophile to give the fused heterocyclic arene. Meanwhile, the 4-unsubstituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene could be converted to the corresponding 4-benzyl-1-naphthol by the Friedel-Crafts 1,6-addition of p-NQM (1-naphthoquinone-4-methide) generated by the site-selective ring opening of the 1,4-epoxy moiety. Furthermore, the 4-(siloxymethyl)-(1,4-bis(siloxymethyl))-1,4-epoxy-1,4-dihydronaphthalene was transformed into a 2,4-bisbenzyl-1-naphthol or pentacyclic derivative via both the o- and p-NQM intermediates.

  19. A study on the properties and reactivity of naphthoquinone-cobalt(III) prototypes for bioreductive prodrugs.

    PubMed

    Bustamante, Francisco L S; Miranda, Fabio S; Castro, Frederico A V; Resende, Jackson A L C; Pereira, Marcos D; Lanznaster, Mauricio

    2014-03-01

    Our group has recently initiated a study on the development of new prototypes for bioreductive prodrugs, based on Co(III) complexes with the ligand 2,2'-bis(3-hydroxy-1,4-naphthoquinone), H2bhnq. The focus of this work is to investigate the dissociation of bhnq(-2) from the complex upon reduction, and the effects of pH, redox potential, oxygen concentration and nature of the auxiliary ligands on this reaction. The bhnq(2-) ligand is a "non-cytotoxic" agent that was chosen as a probe for the reactivity studies due to its suitable chromophoric properties, at the same time that it resembles more cytotoxic naphthoquinones relevant for cancer therapy. In this way, two Co(III) complexes [Co(bhnq)(L1)]BF4·H2O (1) and [Co(bhnq)(L2)]BF4·H2O (2) (L1=N,N'-bis(pyridin-2-ylmethyl)ethylenediamine and L2=N,N'-dimethyl-N,N'-bis(pyridin-2-ylmethyl)ethylenediamine) were synthesized and fully characterized. The gallium analogs [Ga(bhnq)(L1)]NO3·3H2O (3) and [Ga(bhnq)(L2)]NO3·3H2O (4) were also prepared for helping with the assignments of the redox properties of the cobalt complexes and the structure of 2. Cyclic voltammetry analysis revealed a pH-independent quasi-reversible Co(III)/Co(II) process at -0.22 and -0.08V vs NHE for 1 and 2, respectively. An O2-dependent dissociation of bhnq(2-) was observed for the reaction of 1 with ascorbic acid. For 2, the dissociation of bhnq(2-) was found to be independent on the concentration of O2 and faster than in 1, with little influence of the pH on both complexes. The difference in reactivity between 1 and 2 and their redox properties, among other factors, suggests that 1 undergoes redox cycling, pointed out as a key feature for a prodrug to achieve hypoxic selectivity.

  20. Glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones--a new strategy to combat malarial parasites.

    PubMed

    Müller, Tobias; Johann, Laure; Jannack, Beate; Brückner, Margit; Lanfranchi, Don Antoine; Bauer, Holger; Sanchez, Cecilia; Yardley, Vanessa; Deregnaucourt, Christiane; Schrével, Joseph; Lanzer, Michael; Schirmer, R Heiner; Davioud-Charvet, Elisabeth

    2011-08-01

    Our work on targeting redox equilibria of malarial parasites propagating in red blood cells has led to the selection of six 1,4-naphthoquinones, which are active at nanomolar concentrations against the human pathogen Plasmodium falciparum in culture and against Plasmodium berghei in infected mice. With respect to safety, the compounds do not trigger hemolysis or other signs of toxicity in mice. Concerning the antimalarial mode of action, we propose that the lead benzyl naphthoquinones are initially oxidized at the benzylic chain to benzoyl naphthoquinones in a heme-catalyzed reaction within the digestive acidic vesicles of the parasite. The major putative benzoyl metabolites were then found to function as redox cyclers: (i) in their oxidized form, the benzoyl metabolites are reduced by NADPH in glutathione reductase-catalyzed reactions within the cytosols of infected red blood cells; (ii) in their reduced forms, these benzoyl metabolites can convert methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Studies on a fluorinated suicide-substrate indicate as well that the glutathione reductase-catalyzed bioactivation of naphthoquinones is essential for the observed antimalarial activity. In conclusion, the antimalarial naphthoquinones are suggested to perturb the major redox equilibria of the targeted infected red blood cells, which might be removed by macrophages. This results in development arrest and death of the malaria parasite at the trophozoite stage.

  1. Production of naphthoquinones and phenolics by a novel isolate Fusarium solani PSC-R of Palk Bay and their industrial applications.

    PubMed

    Rathna, Janarthanam; Yazhini, Kumanan Bharathi; Ajilda, Antony Alex Kennedy; Prabu, Halliah Guru Mallesh; Pandian, Shunmugiah Karutha

    2016-08-01

    The present study was attempted to enhance the production of naphthoquinones and phenolics by Fusarium solani PSC-R of Palk Bay origin, which exhibited potent antibacterial, antioxidant and dyeing activity. Maximum productivity of naphthoquinones and phenolics was achieved in potato infusion medium supplemented with 2% sucrose. Addition of nitrogen sources to the medium adversely affected the production of both naphthoquinones and phenolics. An initial pH of 5 and incubation at 31°C for six days at 140rpm was found to increase the yield (123.65mg/g of DW), concentration (867.33mg/l) and total naphthoquinones (602.8μM/g DW) by 7.58, 10.44 and 3.68-fold respectively. Similarly, the antioxidant and antibacterial activity associated with the phenolics of PSC-R increased by 1.5-fold in the optimized medium. The obtained results document the effective means of enhanced production of naphthoquinones and phenolics in the suspension culture of F. solani PSC-R at bioreactor level.

  2. Herbicidal action of 2-hydroxy-3-alkyl-1,4-naphthoquinones.

    PubMed

    Jewess, Philip J; Higgins, James; Berry, Kate J; Moss, Stephen R; Boogaard, Adrian B; Khambay, Bhupinder P S

    2002-03-01

    The main mode of herbicidal activity of 2-hydroxy-3-alkyl-1,4-naphthoquinones is shown to be inhibition of photosystem II (PSII). The herbicidal and in vitro activities have been measured and correlated with their (Log)octanol/water partition coefficients (Log Ko/w). The length of the 3-n-alkyl substituent for optimal activity differed between herbicidal and in vitro activity. The maximum in vitro activity was given by the nonyl to dodecyl homologues (Log Ko/w between 6.54 and 8.12), whereas herbicidal activity peaked with the n-hexyl compound (Log Ko/w = 4.95). The effect of chain branching was also investigated using isomeric pentyl analogues substituted at position 3. All exhibited similar levels of in vitro activities but herbicidal activities differed, albeit moderately, with the exception of one analogue that was much less phytotoxic. Other modes of action were also investigated using two representative compounds. They did not show any activity on photosystem I or mitochondrial complex I, or generate toxic oxygen radicals by redox cycling reactions. Only moderate activity was found against mitochondrial complex III from plants, in contrast to much higher corresponding activity using an insect enzyme.

  3. Novel 1,4-naphthoquinone-based sulfonamides: Synthesis, QSAR, anticancer and antimalarial studies.

    PubMed

    Pingaew, Ratchanok; Prachayasittikul, Veda; Worachartcheewan, Apilak; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

    2015-10-20

    A novel series of 1,4-naphthoquinones (33-44) tethered by open and closed chain sulfonamide moieties were designed, synthesized and evaluated for their cytotoxic and antimalarial activities. All quinone-sulfonamide derivatives displayed a broad spectrum of cytotoxic activities against all of the tested cancer cell lines including HuCCA-1, HepG2, A549 and MOLT-3. Most quinones (33-36 and 38-43) exerted higher anticancer activity against HepG2 cell than that of the etoposide. The open chain analogs 36 and 42 were shown to be the most potent compounds. Notably, the restricted sulfonamide analog 38 with 6,7-dimethoxy groups exhibited the most potent antimalarial activity (IC₅₀ = 2.8 μM). Quantitative structure-activity relationships (QSAR) study was performed to reveal important chemical features governing the biological activities. Five constructed QSAR models provided acceptable predictive performance (Rcv 0.5647-0.9317 and RMSEcv 0.1231-0.2825). Four additional sets of structurally modified compounds were generated in silico (34a-34d, 36a-36k, 40a-40d and 42a-42k) in which their activities were predicted using the constructed QSAR models. A comprehensive discussion of the structure-activity relationships was made and a set of promising compounds (i.e., 33, 36, 38, 42, 36d, 36f, 42e, 42g and 42f) was suggested for further development as anticancer and antimalarial agents. PMID:26397393

  4. Cell-specific production and antimicrobial activity of naphthoquinones in roots of lithospermum erythrorhizon

    PubMed

    Brigham; Michaels; Flores

    1999-02-01

    Pigmented naphthoquinone derivatives of shikonin are produced at specific times and in specific cells of Lithospermum erythrorhizon roots. Normal pigment development is limited to root hairs and root border cells in hairy roots grown on "noninducing" medium, whereas induction of additional pigment production by abiotic (CuSO4) or biotic (fungal elicitor) factors increases the amount of total pigment, changes the ratios of derivatives produced, and initiates production of pigment de novo in epidermal cells. When the biological activity of these compounds was tested against soil-borne bacteria and fungi, a wide range of sensitivity was recorded. Acetyl-shikonin and beta-hydroxyisovaleryl-shikonin, the two most abundant derivatives in both Agrobacterium rhizogenes-transformed "hairy-root" cultures and greenhouse-grown plant roots, were the most biologically active of the seven compounds tested. Hyphae of the pathogenic fungi Rhizoctonia solani, Pythium aphanidermatum, and Nectria hematococca induced localized pigment production upon contact with the roots. Challenge by R. solani crude elicitor increased shikonin derivative production 30-fold. We have studied the regulation of this suite of related, differentially produced, differentially active compounds to understand their role(s) in plant defense at the cellular level in the rhizosphere.

  5. A Rare Class of New Dimeric Naphthoquinones from Diospyros lotus have Multidrug Reversal and Antiproliferative Effects

    PubMed Central

    Rauf, Abdur; Uddin, Ghias; Siddiqui, Bina S.; Molnár, Joseph; Csonka, Ákos; Ahmad, Bashir; Szabó, Diana; Farooq, Umar; Khan, Ajmal

    2015-01-01

    Three new dimeric naphthoquinones, 5,4′-dihydroxy-1′-methoxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,5′,8′-tetraone (1), 5′,8′-dihydroxy-5-methoxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,1′,4′-tetraone (2) and 8,5′,8′-trihydroxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,1′,4′-tetraone (3), were isolated from the roots of Diospyros lotus. Their structures were elucidated by spectroscopic techniques, including 1D and 2D NMR, such as HSQC, HMBS, NOESY, and J-resolved. Compounds 1–3 were evaluated for their effects on the reversion of multidrug resistance (MDR) mediated by P-glycoprotein through use of the rhodamine-123 exclusion screening test on human ABCB1 gene transfected L5178Y mouse T-cell lymphoma. Compounds 1–3 were also assessed for their antiproliferative and cytotoxic effects on L5178 and L5178Y mouse T-cell lymphoma lines. Both 1 and 2 exhibited promising antiproliferative and MDR-reversing effects in a dose-dependent manner. The effects of the tested compounds on the activity of doxorubicin were observed to vary from slight antagonism to antagonism. PMID:26732580

  6. Biosynthesis and molecular actions of specialized 1,4-naphthoquinone natural products produced by horticultural plants.

    PubMed

    Widhalm, Joshua R; Rhodes, David

    2016-01-01

    The 1,4-naphthoquinones (1,4-NQs) are a diverse group of natural products found in every kingdom of life. Plants, including many horticultural species, collectively synthesize hundreds of specialized 1,4-NQs with ecological roles in plant-plant (allelopathy), plant-insect and plant-microbe interactions. Numerous horticultural plants producing 1,4-NQs have also served as sources of traditional medicines for hundreds of years. As a result, horticultural species have been at the forefront of many basic studies conducted to understand the metabolism and function of specialized plant 1,4-NQs. Several 1,4-NQ natural products derived from horticultural plants have also emerged as promising scaffolds for developing new drugs. In this review, the current understanding of the core metabolic pathways leading to plant 1,4-NQs is provided with additional emphasis on downstream natural products originating from horticultural species. An overview on the biochemical mechanisms of action, both from an ecological and pharmacological perspective, of 1,4-NQs derived from horticultural plants is also provided. In addition, future directions for improving basic knowledge about plant 1,4-NQ metabolism are discussed. PMID:27688890

  7. Beyond topoisomerase inhibition: antitumor 1,4-naphthoquinones as potential inhibitors of human monoamine oxidase.

    PubMed

    Coelho-Cerqueira, Eduardo; Netz, Paulo A; do Canto, Vanessa P; Pinto, Angelo C; Follmer, Cristian

    2014-04-01

    Monoamine oxidase (MAO) action has been involved in the regulation of neurotransmitters levels, cell signaling, cellular growth, and differentiation as well as in the balance of the intracellular polyamine levels. Although so far obscure, MAO inhibitors are believed to have some effect on tumors progression. 1,4-naphthoquinone (1,4-NQ) has been pointed out as a potential pharmacophore for inhibition of both MAO and DNA topoisomerase activities, this latter associated with antitumor activity. Herein, we demonstrated that certain antitumor 1,4-NQs, including spermidine-1,4-NQ, lapachol, and nor-lapachol display inhibitory activity on human MAO-A and MAO-B. Kinetic studies indicated that these compounds are reversible and competitive MAO inhibitors, being the enzyme selectivity greatly affected by substitutions on 1,4-NQ ring. Molecular docking studies suggested that the most potent MAO inhibitors are capable to bind to the MAO active site in close proximity of flavin moiety. Furthermore, ability to inhibit both MAO-A and MAO-B can be potentialized by the formation of hydrogen bonds between these compounds and FAD and/or the residues in the active site. Although spermidine-1,4-NQs exhibit antitumor action primarily by inhibiting topoisomerase via DNA intercalation, our findings suggest that their effect on MAO activity should be taken into account when their application in cancer therapy is considered.

  8. Biosynthesis and molecular actions of specialized 1,4-naphthoquinone natural products produced by horticultural plants.

    PubMed

    Widhalm, Joshua R; Rhodes, David

    2016-01-01

    The 1,4-naphthoquinones (1,4-NQs) are a diverse group of natural products found in every kingdom of life. Plants, including many horticultural species, collectively synthesize hundreds of specialized 1,4-NQs with ecological roles in plant-plant (allelopathy), plant-insect and plant-microbe interactions. Numerous horticultural plants producing 1,4-NQs have also served as sources of traditional medicines for hundreds of years. As a result, horticultural species have been at the forefront of many basic studies conducted to understand the metabolism and function of specialized plant 1,4-NQs. Several 1,4-NQ natural products derived from horticultural plants have also emerged as promising scaffolds for developing new drugs. In this review, the current understanding of the core metabolic pathways leading to plant 1,4-NQs is provided with additional emphasis on downstream natural products originating from horticultural species. An overview on the biochemical mechanisms of action, both from an ecological and pharmacological perspective, of 1,4-NQs derived from horticultural plants is also provided. In addition, future directions for improving basic knowledge about plant 1,4-NQ metabolism are discussed.

  9. A Rare Class of New Dimeric Naphthoquinones from Diospyros lotus have Multidrug Reversal and Antiproliferative Effects.

    PubMed

    Rauf, Abdur; Uddin, Ghias; Siddiqui, Bina S; Molnár, Joseph; Csonka, Ákos; Ahmad, Bashir; Szabó, Diana; Farooq, Umar; Khan, Ajmal

    2015-01-01

    Three new dimeric naphthoquinones, 5,4'-dihydroxy-1'-methoxy-6,6'-dimethyl-7,3'-binaphthyl-1,4,5',8'-tetraone (1), 5',8'-dihydroxy-5-methoxy-6,6'-dimethyl-7,3'-binaphthyl-1,4,1',4'-tetraone (2) and 8,5',8'-trihydroxy-6,6'-dimethyl-7,3'-binaphthyl-1,4,1',4'-tetraone (3), were isolated from the roots of Diospyros lotus. Their structures were elucidated by spectroscopic techniques, including 1D and 2D NMR, such as HSQC, HMBS, NOESY, and J-resolved. Compounds 1-3 were evaluated for their effects on the reversion of multidrug resistance (MDR) mediated by P-glycoprotein through use of the rhodamine-123 exclusion screening test on human ABCB1 gene transfected L5178Y mouse T-cell lymphoma. Compounds 1-3 were also assessed for their antiproliferative and cytotoxic effects on L5178 and L5178Y mouse T-cell lymphoma lines. Both 1 and 2 exhibited promising antiproliferative and MDR-reversing effects in a dose-dependent manner. The effects of the tested compounds on the activity of doxorubicin were observed to vary from slight antagonism to antagonism. PMID:26732580

  10. Surface enhanced Raman spectral studies of 2-bromo-1,4-naphthoquinone.

    PubMed

    Geetha, K; Umadevi, M; Sathe, G V; Vanelle, P; Terme, T; Khoumeri, O

    2015-03-01

    Silver nanoparticles have been synthesized by a simple and inexpensive solution combustion method with urea as fuel. The structural and morphology of the silver nanoparticles were investigated through X-ray powder diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersion Spectra (EDS) techniques. Structural and morphological results confirmed the nanocrystalline nature of the silver nanoparticles. Density Functional Theory (DFT) calculations were also performed to study the ground and excited state behavior of 2-bromo-1,4-naphthoquinone (2-BrNQ) and 2-BrNQ on silver nanoparticles. Surface-Enhanced Raman Scattering (SERS) spectra of 2-BrNQ adsorbed on silver nanoparticles were investigated. The CO, CH in-plane bending and CBr stretching modes were enhanced in SERS spectrum with respect to normal Raman spectrum. The spectral analysis reveals that the 2-BrNQ adsorbed 'stand-on' orientation on the silver surface. Density Functional Theory (DFT) calculations are also performed to study the vibrational features of 2-BrNQ molecule and 2-BrNQ molecule on silver surface. PMID:25481490

  11. Synthesis and cytotoxic evaluation of a series of 2-amino-naphthoquinones against human cancer cells.

    PubMed

    de Moraes, Thiago A P; Filha, Maria J S; Camara, Celso A; Silva, Tania M S; Soares, Bruno M; Bomfim, Igor S; Pessoa, Claudia; Ximenes, George C; Silva Junior, Valdemiro A

    2014-08-26

    The cytotoxicity of a series of aminonaphthoquinones resulting from the reaction of suitable aminoacids with 1,4-naphthoquinone was assayed against SF-295 (glioblastoma), MDAMB-435 (breast), HCT-8 (colon), HCT-116 (colon), HL-60 (leukemia), OVCAR-8 (ovarian), NCI-H358M (bronchoalveolar lung carcinoma) and PC3-M (prostate) cancer cells and also against PBMC (peripheral blood mononuclear cells). The results demonstrated that all the synthetic aminonaphthoquinones had relevant cytotoxic activity against all human cancer lines used in this experiment. Five of the compounds showed high cytotoxicity and selectivity against all cancer cell lines tested (IC50 = 0.49 to 3.89 µg·mL-1). The title compounds were less toxic to PBMC, since IC50 was 1.5 to eighteen times higher (IC50 = 5.51 to 17.61 µg·mL-1) than values shown by tumour cell lines. The mechanism of cell growth inhibition and structure-activity relationships remains as a target for future investigations.

  12. Proteomics Analyses of Bacillus subtilis after Treatment with Plumbagin, a Plant-Derived Naphthoquinone

    PubMed Central

    Reddy, Panga Jaipal; Ray, Sandipan; Sathe, Gajanan J.; Prasad, T.S. Keshava; Rapole, Srikanth; Panda, Dulal

    2015-01-01

    Abstract Infectious diseases and increasing antibiotic resistance among diverse classes of microbes are global health concerns and a prime focus of omics systems science applications in novel drug discovery. Plumbagin is a plant-derived naphthoquinone, a natural product that exhibits antibacterial activity against gram-positive bacteria. In the present study, we investigated the antimicrobial effects of plumbagin against Bacillus subtilis using two complementary proteomics techniques: two-dimensional electrophoresis (2-DE) and isobaric tag for relative and absolute quantification (iTRAQ). Comparative quantitative proteomics analysis of plumbagin treated and untreated control samples identified differential expression of 230 proteins (1% FDR, 1.5 fold-change and ≥2 peptides) in B. subtilis after plumbagin treatment. Pathway analysis involving the differentially expressed proteins suggested that plumbagin effectively increases heme and protein biosynthesis, whereas fatty acid synthesis was significantly reduced. Gene expression and metabolic activity assays further corroborated the proteomics findings. We anticipate that plumbagin blocks the cell division by altering the membrane permeability required for energy generation. This is the first report, to the best of our knowledge, offering new insights, at proteome level, for the putative mode(s) of action of plumbagin and attendant cellular targets in B. subtilis. The findings also suggest new ways forward for the modern omics-guided drug target discovery, building on traditional plant medicine. PMID:25562197

  13. Biosynthesis and molecular actions of specialized 1,4-naphthoquinone natural products produced by horticultural plants

    PubMed Central

    Widhalm, Joshua R; Rhodes, David

    2016-01-01

    The 1,4-naphthoquinones (1,4-NQs) are a diverse group of natural products found in every kingdom of life. Plants, including many horticultural species, collectively synthesize hundreds of specialized 1,4-NQs with ecological roles in plant–plant (allelopathy), plant–insect and plant–microbe interactions. Numerous horticultural plants producing 1,4-NQs have also served as sources of traditional medicines for hundreds of years. As a result, horticultural species have been at the forefront of many basic studies conducted to understand the metabolism and function of specialized plant 1,4-NQs. Several 1,4-NQ natural products derived from horticultural plants have also emerged as promising scaffolds for developing new drugs. In this review, the current understanding of the core metabolic pathways leading to plant 1,4-NQs is provided with additional emphasis on downstream natural products originating from horticultural species. An overview on the biochemical mechanisms of action, both from an ecological and pharmacological perspective, of 1,4-NQs derived from horticultural plants is also provided. In addition, future directions for improving basic knowledge about plant 1,4-NQ metabolism are discussed. PMID:27688890

  14. Biosynthesis and molecular actions of specialized 1,4-naphthoquinone natural products produced by horticultural plants

    PubMed Central

    Widhalm, Joshua R; Rhodes, David

    2016-01-01

    The 1,4-naphthoquinones (1,4-NQs) are a diverse group of natural products found in every kingdom of life. Plants, including many horticultural species, collectively synthesize hundreds of specialized 1,4-NQs with ecological roles in plant–plant (allelopathy), plant–insect and plant–microbe interactions. Numerous horticultural plants producing 1,4-NQs have also served as sources of traditional medicines for hundreds of years. As a result, horticultural species have been at the forefront of many basic studies conducted to understand the metabolism and function of specialized plant 1,4-NQs. Several 1,4-NQ natural products derived from horticultural plants have also emerged as promising scaffolds for developing new drugs. In this review, the current understanding of the core metabolic pathways leading to plant 1,4-NQs is provided with additional emphasis on downstream natural products originating from horticultural species. An overview on the biochemical mechanisms of action, both from an ecological and pharmacological perspective, of 1,4-NQs derived from horticultural plants is also provided. In addition, future directions for improving basic knowledge about plant 1,4-NQ metabolism are discussed.

  15. Double mode of inhibition-inducing interactions of 1,4-naphthoquinone with urease: arylation versus oxidation of enzyme thiols.

    PubMed

    Krajewska, Barbara; Zaborska, Wiesława

    2007-06-15

    In their inhibition-inducing interactions with enzymes, quinones primarily utilize two mechanisms, arylation and oxidation of enzyme thiol groups. In this work, we investigated the interactions of 1,4-naphthoquinone with urease in an effort to estimate the contribution of the two mechanisms in the enzyme inhibition. Jack bean urease, a homohexamer, contains 15 thiols per enzyme subunit, six accessible under non-denaturing conditions, of which Cys592 proximal to the active site indirectly participates in the enzyme catalysis. Unlike by 1,4-benzoquinone, a thiol arylator, the inactivation of urease by 1,4-naphthoquinone under aerobic conditions was found to be biphasic, time- and concentration-dependent with a non-linear residual activity-modified thiols dependence. DTT protection studies and thiol titration with DTNB suggest that thiols are the sites of enzyme interactions with the quinone. The inactivated enzyme had approximately 40% of its activity restored by excess DTT supporting the presence of sulfenic acid resulting from the oxidation of enzyme thiols by ROS. Furthermore, the aerobic inactivation was prevented in approximately 30% by catalase, proving the involvement of hydrogen peroxide in the process. When H2O2 was directly applied to urease, the enzyme showed susceptibility to this inactivation in a time- and concentration-dependent manner with the inhibition constant of H2O2 Ki = 3.24 mM. Additionally, anaerobic inactivation of urease was performed and was found to be weaker than aerobic. The results obtained are consistent with a double mode of 1,4-naphthoquinone inhibitory action on urease, namely through the arylation of the enzyme thiol groups and ROS generation, notably H2O2, resulting in the oxidation of the groups. PMID:17416528

  16. Hydroxyl radical generation mechanism during the redox cycling process of 1,4-naphthoquinone.

    PubMed

    Shang, Yu; Chen, Chenyong; Li, Yi; Zhao, Jincai; Zhu, Tong

    2012-03-01

    Airborne quinones contribute to adverse health effects of ambient particles probably because of their ability to generate hydroxyl radicals (·OH) via redox cycling, but the mechanisms remain unclear. We examined the chemical mechanisms through which 1,4-naphthoquinone (1,4-NQ) induced ·OH, and the redox interactions between 1,4-NQ and ascorbate acid (AscH(2)). First, ·OH formation by 1,4-NQ was observed in cellular and acellular systems, and was enhanced by AscH(2). AscH(2) also exacerbated the cytotoxicity of 1,4-NQ in Ana-1 macrophages, at least partially due to enhanced ·OH generation. The detailed mechanism was studied in an AscH(2)/H(2)O(2) physiological system. The existence of a cyclic 1,4-NQ process was shown by detecting the corresponding semiquinone radical (NSQ·-) and hydroquinone (NQH(2)). 1,4-NQ was reduced primarily to NSQ·- by O2·- (which was from AscH(2) reacting with H(2)O(2)), not by AscH(2) as normally thought. At lower doses, 1,4-NQ consumed O2·- to suppress ·OH; however, at higher doses, 1,4-NQ presented a positive association with ·OH. The reaction of NSQ·- with H(2)O(2) to release ·OH was another important channel for OH radical formation except for Haber-Weiss reaction. As a reaction precursor for O2·-, the enhanced ·OH response to 1,4-NQ by AscH(2) was indirect. Reducing substrates were necessary to sustain the redox cycling of 1,4-NQ, leading to more ·OH and a deleterious end point.

  17. Ex vivo effects of naphthoquinones on allergen-sensitized mononuclear cells in mice.

    PubMed

    Tanaka, M; Inoue, K; Shimada, A; Takano, H

    2016-09-01

    Naphthoquinone (NQ), one of the extractable chemical compounds of diesel exhaust particles, enhances allergic asthma traits in mice. However, it remains unknown whether: (1) several types of NQs have the same potential to facilitate allergies; and (2) NQs synergistically disrupt the functional phenotypes of immune cells. The aim of the present study was to investigate the effects of two types (1,2- and 1,4-) of NQs on sensitized mononuclear cells using an ex vivo assay. Male BALB/c mice were repeatedly and intraperitoneally administered ovalbumin (OVA: 20 µg) plus alum with or without two different doses of each NQ. After the final administration, splenocytes (mononuclear cells) were isolated from these mice and cultured in the presence of OVA. Helper T-related cytokines in the culture supernatants and downstream molecules were then evaluated. Protein levels of interferon-γ were higher in the supernatants from 1,2-NQ and 1,4-NQ at low dose + OVA-exposed mononuclear cells following the OVA stimulation than in those from OVA-exposed mononuclear cells. Interleukin (IL)-13 levels were higher in the supernatants from low dose NQs + OVA-exposed mononuclear cells. IL-17 levels were significantly higher in the supernatants from low dose 1,2-NQ + OVA-exposed mononuclear cells. The quantity of phosphorylated STAT6 in the nuclei of these cells was significantly greater in the low dose NQ + OVA groups than in the OVA group. These findings suggest NQs differently enhance allergen sensitization in the context of the Th response against mononuclear cells such as lymphocytes. PMID:26884456

  18. Naphthoquinone based chemosensor 2-(2‧-aminomethylpyridine)-3-chloro-1,4-naphthoquinone for metal ions: Single crystal X-ray structure, experimental and TD-DFT study

    NASA Astrophysics Data System (ADS)

    Ware, Anuja P.; Patil, Amit; Khomane, Sonali; Weyhermüller, Thomas; Pingale, Subhash S.; Salunke-Gawali, Sunita

    2015-08-01

    Naphthoquinone based redox active chemosensor 1; 2-(2‧-aminomethylpyridine)-3-chloro-1,4-naphthoquinone ligand has been synthesized and characterized. Chemosensor 1 crystallizes in monoclinic space group P21/n. Molecules showed intramolecular N-H⋯O and N-H⋯N, intermolecular N-H⋯O, C-H⋯O and slipped π-π stacking interactions. Chemosensor 1 showed orange colored solution in methanol and specifically detects Cu2+ ions by deprotonation of N-H. The deprotonation of amino N-H can also be achieved by mild base viz. triethylamine and chemosensor 1 can be used to detect several metal ions for example Ni2+, Mn2+ etc. that could observed by naked eye. Color changes observed were monitored by UV-visible and fluorescence spectra. Chemosensor 1 could provide either bidentate or tridentate coordination sites to metal ions. Redox nature of chemosensor 1 was evaluated by cyclic voltammetry studies. Electronic transition wavelengths of chemosensor 1 ligand have been evaluated in methanol, water and triethylamine by TD-DFT studies and comparative studies were performed with experimental results.

  19. Substituted 3‑acyl‑2‑phenylamino‑1,4‑naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death.

    PubMed

    Farias, Mirelle Sifroni; Pich, Claus Tröger; Kviecinski, Maicon Roberto; Bucker, Nádia Cristina Falcão; Felipe, Karina Bettega; Da Silva, Fabiana Ourique; Günther, Tânia Mara Fisher; Correia, João Francisco; Ríos, David; Benites, Julio; Valderrama, Jaime A; Calderon, Pedro Buc; Pedrosa, Rozangela Curi

    2014-07-01

    Naphthoquinones interact with biological systems by generating reactive oxygen species (ROS) that can damage cancer cells. The cytotoxicity and the antitumor activity of 3‑acyl‑2‑phenylamino‑1,4‑naphthoquinones (DPB1‑DPB9) were evaluated in the MCF7 human breast cancer cell line and in male Ehrlich tumor‑bearing Balb/c mice. DPB4 was the most cytotoxic derivative against MCF7 cells (EC50 15 µM) and DPB6 was the least cytotoxic one (EC50 56 µM). The 1,4‑naphthoquinone derivatives were able to cause DNA damage and promote DNA fragmentation as shown by the plasmid DNA cleavage assay (FII form). In addition, 1,4‑naphthoquinone derivatives possibly interacted with DNA as intercalating agents, which was demonstrated by the changes caused in the fluorescence of the DNA‑ethidium bromide complexes. Cell death of MCF7 cells induced by 3‑acyl‑2‑phenylamino‑1,4‑naphthoquinones was mostly due to apoptosis. The DNA fragmentation and subsequent apoptosis may be correlated to the redox potential of the 1,4‑naphthoquinone derivatives that, once present in the cell nucleus, led to the increased generation of ROS. Finally, certain 1,4‑naphthoquinone derivatives and particularly DPB4 significantly inhibited the growth of Ehrlich ascites tumors in mice (73%). PMID:24756411

  20. A small library of synthetic di-substituted 1, 4-naphthoquinones induces ROS-mediated cell death in murine fibroblasts.

    PubMed

    Ramirez, Oscar; Motta-Mena, Laura B; Cordova, Amanda; Estrada, Abril; Li, Qingyi; Martinez, Luis; Garza, Kristine M

    2014-01-01

    Synthesis of compound libraries and their concurrent assessment as selective reagents for probing and modulating biological function continues to be an active area of chemical biology. Microwave-assisted solid-phase Dötz benzannulation reactions have been used to inexpensively synthesize 2, 3-disubstituted-1, 4-naphthoquinone derivatives. Herein, we report the biological testing of a small library of such compounds using a murine fibroblast cell line (L929). Assessment of cellular viability identified three categories of cytotoxic compounds: no toxicity, low/intermediate toxicity and high toxicity. Increased levels of Annexin-V-positive staining and of caspase 3 activity confirmed that low, intermediate, and highly toxic compounds promote cell death. The compounds varied in their ability to induce mitochondrial depolarization and formation of reactive oxygen species (ROS). Both cytotoxic and non-cytotoxic compounds triggered mitochondrial depolarization, while one highly cytotoxic compound did not. In addition, all cytotoxic compounds promoted increased intracellular ROS but the cells were only partially protected from compound-induced apoptosis when in the presence of superoxide dismutase, catalase, or ascorbic acid suggesting utilization of additional pro-death mechanisms. In summary, nine of twelve (75%) 1, 4-naphthoquinone synthetic compounds were cytotoxic. Although the mitochondria did not appear to be a central target for induction of cell death, all of the cytotoxic compounds induced ROS formation. Thus, the data demonstrate that the synthesis regime effectively created cytotoxic compounds highlighting the potential use of the regime and its products for the identification of biologically relevant reagents. PMID:25197824

  1. Interaction of 2,3-dichloro-1,4-naphthoquinone with n-butylamine in halocarbon solvents

    NASA Astrophysics Data System (ADS)

    Neelgund, Gururaj M.; Budni, M. L.

    2005-06-01

    The rapid interaction between 2,3-dichloro-1,4-naphthoquinone (DClNQ) and n-butylamine results in the formation of 2N( n-butylamino)-3-chloro-1,4-naphthoquinone as the final product. The reaction is found to proceed through the initial formation of charge-transfer (CT) complex as an intermediate. The final product of the reaction has been isolated and characterized using FTIR, H1 and C13 NMR spectroscopy, mass spectrometry, and elemental analysis. The rate of formation of product has been measured as a function of time in different halocarbon solvents, viz., chloroform, dichloromethane and 1:1 (v/v) mixture of two solvents. The pseudo first order and second order rate constants at various temperatures for the transformation process were evaluated from the absorbance time data. The activation parameters ( Ea, Δ S#, Δ H#, and Δ G#) were obtained from temperature dependence of rate constants. The influence of dielectric constant on the properties of reaction was discussed and the probable course of reaction is presented.

  2. Electron donor-acceptor interaction of 3,4-dimethylaniline with 2,3-dicyano-1,4-naphthoquinone

    NASA Astrophysics Data System (ADS)

    Neelgund, Gururaj M.; Magadum, Subash R.; Budni, M. L.

    2011-01-01

    The electron donor-acceptor (EDA) interaction between 2,3-dicyano-1,4-naphthoquinone (DCNQ) and 3,4-dimethylaniline (3,4-DMA) is studied in chloroform, dichloromethane and 1:1 (v/v) mixture of chloroform and dichloromethane. The rate of formation of the product was measured as a function of time using UV-vis spectrophotometer. The formation constant ( K) and molar extinction coefficient ( ɛ) values for the formation of EDA complex were evaluated in the temperature range of 20-35 °C. The pseudo-first-order rate constant ( k1) and the second-order rate constant ( k2) for the disappearance of EDA complex and for the formation of product were evaluated. The activation parameters (Δ H#, Δ S# and Δ G#) of the reaction were determined by temperature dependence of rate constants using the Arrhenius plots. The effect of relative permittivity of the medium on the reaction is discussed. The observed results indicate that formation of final product proceeds through initial formation of EDA complex as an intermediate. The product of the reaction was purified by column chromatography method and identified as 3-( N-3,4-dimethyl-phenylamino)-2-cyano-1,4-naphthoquinone by elemental analysis, IR and NMR spectroscopy. On the basis of kinetic, analytical and spectroscopic results, a plausible mechanism for the formation of EDA complex and its transformation into product is proposed.

  3. A 1,2,3-dithiazolyl-o-naphthoquinone: a neutral radical with isolable cation and anion oxidation states.

    PubMed

    Smithson, Chad S; MacDonald, Daniel J; Matt Letvenuk, T; Carello, Christian E; Jennings, Michael; Lough, Alan J; Britten, James; Decken, Andreas; Preuss, Kathryn E

    2016-06-21

    Under aprotic conditions, the reaction of 4-amino-1,2-naphthoquinone with excess S2Cl2 generates 4,5-dioxo-naphtho[1,2-d][1,2,3]dithiazol-2-ium chloride in a typical Herz condensation. By contrast, prior literature reports an imine (NH) product, 4,5-dioxo-1H-naphtho[1,2-d][1,2,3]dithiazole, for the same reaction performed in acetic acid. Herein, the cation product is isolated with four different counter-anions (Cl(-), GaCl4(-), FeCl4(-) and OTf(-)). Reduction of the cation generates a neutral radical 1,2,3-dithiazolyl-o-naphthoquinone, with potential ligand properties. Further reduction generates a closed shell anion, isolated as a water-stable Li(+) complex and exhibiting O,O-bidentate chelation. The hydroxy (OH) isomer of the original imine (NH) product is reported, and this can be readily deprotonated and acylated (OAc). All species are structurally characterized. Solution redox behaviour and EPR are discussed where appropriate. PMID:27216412

  4. Tautomerism in o-hydroxyanilino-1,4-naphthoquinone derivatives: Structure, NMR, HPLC and density functional theoretic investigations

    NASA Astrophysics Data System (ADS)

    Bhand, Sujit; Patil, Rishikesh; Shinde, Yogesh; Lande, Dipali N.; Rao, Soniya S.; Kathawate, Laxmi; Gejji, Shridhar P.; Weyhermüller, Thomas; Salunke-Gawali, Sunita

    2016-11-01

    Structure and spectral characteristics of 'Ortho' ((E)-4-hydroxy-2-(2‧-(4‧-R)-hydroxyphenyl)-imino)-naphthalen-1(2H)-one) and 'para' (2-(2‧-(4‧-R)-hydroxyphenyl)-amino)-1,4-naphthoquinone) tautomers of o-hydroxyanilino-1,4-naphthoquinone derivatives (Rdbnd H, 1A; sbnd CH3, 2A; and -Cl, 3A) are investigated using the 1H, 13C, DEPT, gDQCOSY, gHSQCAD NMR, HPLC, cyclic voltammetry techniques combined with the density functional theory. The compound 2A crystallizes in monoclinic space group P21/c. wherein the polymer chain is facilitated via Osbnd H⋯O and Csbnd H⋯O intermolecular hydrogen bonding. Marginal variations in bond distances in quinonoid and aminophenol moieties render structural flexibility to these compounds those in solution exist as exist in 'ortho - para' tautomers. 1H and 13C NMR spectra in DMSO-d6 showed two sets of peaks in all compounds; whereas only the para tautomer of for 1A and 2A, the para tautomer is predominant in CD3CN solution. Further the ortho-para interconversion is accompanied by a large up-field signals for C(3)sbnd H(3) in their 1H and 13C NMR spectra. These inferences are corroborated by the density functional theoretic calculations.

  5. A small library of synthetic di-substituted 1, 4-naphthoquinones induces ROS-mediated cell death in murine fibroblasts.

    PubMed

    Ramirez, Oscar; Motta-Mena, Laura B; Cordova, Amanda; Estrada, Abril; Li, Qingyi; Martinez, Luis; Garza, Kristine M

    2014-01-01

    Synthesis of compound libraries and their concurrent assessment as selective reagents for probing and modulating biological function continues to be an active area of chemical biology. Microwave-assisted solid-phase Dötz benzannulation reactions have been used to inexpensively synthesize 2, 3-disubstituted-1, 4-naphthoquinone derivatives. Herein, we report the biological testing of a small library of such compounds using a murine fibroblast cell line (L929). Assessment of cellular viability identified three categories of cytotoxic compounds: no toxicity, low/intermediate toxicity and high toxicity. Increased levels of Annexin-V-positive staining and of caspase 3 activity confirmed that low, intermediate, and highly toxic compounds promote cell death. The compounds varied in their ability to induce mitochondrial depolarization and formation of reactive oxygen species (ROS). Both cytotoxic and non-cytotoxic compounds triggered mitochondrial depolarization, while one highly cytotoxic compound did not. In addition, all cytotoxic compounds promoted increased intracellular ROS but the cells were only partially protected from compound-induced apoptosis when in the presence of superoxide dismutase, catalase, or ascorbic acid suggesting utilization of additional pro-death mechanisms. In summary, nine of twelve (75%) 1, 4-naphthoquinone synthetic compounds were cytotoxic. Although the mitochondria did not appear to be a central target for induction of cell death, all of the cytotoxic compounds induced ROS formation. Thus, the data demonstrate that the synthesis regime effectively created cytotoxic compounds highlighting the potential use of the regime and its products for the identification of biologically relevant reagents.

  6. Transition metal quinone-thiosemicarbazone complexes 3: Spectroscopic characterizations of spin-mixed iron (III) of naphthoquinone-thiosemicarbazones.

    PubMed

    Chikate, Rajeev C; Padhye, Subhash B

    2007-04-01

    An interesting series of iron (III) complexes with naphthoquinone-thiosemicarbazones are synthesized and physico-chemically characterized by elemental analysis, UV-vis, IR, EPR and magnetic susceptibility measurements. They possess a cationic octahedral [FeL2]+ species and a tetrahedral [FeCl4]- anion and exhibit unusual spin-mixed states involving high-spin and low-spin ferric centers as revealed from magnetic behavior with significant amount of exchange interactions mediated by intermolecular associations. The magnetic susceptibility data is fitted with S1=5/2 and S2=1/2 Heisengberg's exchange coupled model; H=-2JS1S2 and the magnetic exchange interactions are found to be of the order of -13.6 cm-1 indicating the moderate coupling between two paramagnetic centers present in different chemical and structural environment. The presence of spin-paired iron (III) cation having dxz2dxz2dxz1 ground state is revealed from the EPR spectra with three prominent peaks while the high-spin tetrahedral iron (III) anion exhibits characteristics g=4 signal whose intensity increases with lowering the temperature suggesting its influence on the magnetic properties of the complex molecule. FTIR measurements indicate tridentate ONS donor systems involving quinone/hydroxyl oxygen, imine/hydrazinic nitrogen and thione/thiol sulfur atoms as binding sites for naphthoquinone-thiosemicarbazones. PMID:16876470

  7. Solid-phase organic synthesis of 2-tridecanyl-1,4-naphthoquinone and 2-tridecanyl-1,4-naphthodiol that form redox-active micelles and vesicles.

    PubMed

    Bugarin, Alejandro; Martinez, Luis E; Cooke, Peter; Islam, Tadiqul; Noveron, Juan C

    2014-10-01

    The solid-phase synthesis of new amphiphilic compounds is reported. It is based on a newly designed 1,4-naphthoquinone derivative that contains polar and nonpolar groups and self-assembles into micelles or vesicles in water depending on the concentration. They also display redox-active properties.

  8. Molecular association of 2-(n-alkylamino)-1,4-naphthoquinone derivatives: Electrochemical, DFT studies and antiproliferative activity against leukemia cell lines

    NASA Astrophysics Data System (ADS)

    Patil, Rishikesh; Bhand, Sujit; Konkimalla, V. Badireenath; Banerjee, Priyabrata; Ugale, Bharat; Chadar, Dattatray; Saha, Sourav Kr.; Praharaj, Prakash Priyadarshi; Nagaraja, C. M.; Chakrovarty, Debamitra; Salunke-Gawali, Sunita

    2016-12-01

    Molecular structures and their molecular association of 2-(n-alkylamino)-1,4-naphthoquinone, viz., LH-3; propyl, LH-4; butyl and LH-8; octyl derivatives were studied by single crystal X-ray diffraction studies. Synthesis and characterization of 2-octylamino-1,4-naphthoquinone; LH-8 was discussed. The molecule of LH-3 crystallizes in orthorhombic space group P21/c, while the LH-4 and LH-8 molecule crystallizes in triclinic space group P-1. LH-3, LH-4 and LH-8 showed intermolecular N-H⋯O and C-H⋯O interactions, LH-3 showed unique C(3)-H(3)⋯O(1) interaction. Interchain π-π stacking, slipped π-π stacking and C⋯O close contacts was respectively observed in LH-3, LH-4 and LH-8. Electrochemical studies were performed on first eight members of homologous series of 2-(n-alkylamino)-1,4-naphthoquinone (LH-1 to LH-8) by cyclic voltammetry. Naphthoquinone to naphthosemiquinone reversible redox couple was observed in all compounds ∼ E1/2 = -0.657 ± 0.05 V. HOMO-LUMO band gap was determined for the neutral form as well as the monoanionic radical form viz. naphthosemiquinone form of selected derivatives by DFT studies. It has been observed that the electron density is delocalized in the naphthoquinone ring in both neutral as well as one electron reduced form of compounds. Antiproliferative activity of LH-1 to LH-8 was evaluated against two cancer cell lines, THP1(acute monocytic leukemia) and K562(human immortalized myelogenous leukemia cell line) cells. It was observed that, in THP1 cells, compounds LH-2 and LH-3 are very active while LH-1, LH-4 and LH-6 were moderately active and LH-5, LH-7 and LH-8 were totally inactive. Contrastingly, in K562 cells all of the compounds were moderately active.

  9. Evaluation of selected benzoquinones, naphthoquinones, and anthraquinones as replacements for phylloquinone in the A sub 1 acceptor site of the photosystem I reaction center

    SciTech Connect

    Biggins, J. )

    1990-08-07

    Selected substituted 1,4-benzoquinones, 1,4-naphthoquinones, and 9,10-anthraquinones were investigated as possible replacement quinones in spinach photosystem I (PSI) preparations that had been depleted of endogenous phylloquinone by extraction with hexane/methanol. As a criterion for successful biochemical reconstitution, the restoration of electron transfer was determined by measuring P-430 turnover at room temperature from flash-induced absorbance transients. Restoration of complete electron transfer between A{sub 0}{sup {minus}} and P-430 (terminal iron-sulfur centers, F{sub A}F{sub B}) was demonstrated by using phylloquinone, 2-methyl-3-decyl-1,4-naphthoquinone, 2-methyl-3-(isoprenyl){sub 2}-1,4-naphthoquinone, and 2-methyl-3-(isoprenyl){sub 4}-1,4-naphthoquinone. All other quinones tested did not restore P-430 turnover but acted as electron acceptors and oxidized A{sub 0}{sup {minus}}. It is concluded that the specificity of the replacement quinone for interaction with the primary acceptor, A{sub 0}{sup {minus}}, is low but additional structural constraints are required for the quinone occupying the A{sub 1} site to donate to the iron-sulfur center, F{sub x}. It is suggested that the 3-phytyl side chain of phylloquinone and the 3-alkyl tails of the three naphthoquinones that restored P-430 turnover may be required for interaction with a hydrophobic domain of the A{sub 1} site in the PSI core to promote electron transfer to F{sub x} and then to F{sub A}F{sub B}.

  10. Anti-proliferative actions of 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone in vascular smooth muscle cells

    SciTech Connect

    Lee, Jung-Jin; Zhang, Wei-Yun; Yi, Hyoseok; Kim, Yohan; Kim, In-Su; Shen, Gui-Nan; Song, Gyu-Yong; Myung, Chang-Seon

    2011-07-22

    Highlights: {yields} 2-Decylamino-DMNQ inhibited PDGF-BB-induced VSMC proliferation in a dose-dependent manner with no apparent cytotoxicity. {yields} 2-Decylamino-DMNQ inhibited PDGF-BB-induced phosphorylation of Erk1/2 and PLC{gamma}1. {yields} 2-Decylamino-DMNQ arrested a G{sub 0}/G{sub 1} cell cycle progression in association with pRb phosphorylation and PCNA expression. {yields} Both U0126, an Erk inhibitor, and U73122, a PLC{gamma} inhibitor, arrested a G{sub 0}/G{sub 1} phase of the cell cycle. -- Abstract: Naphthoquinone derivatives have been reported to possess various pharmacological activities, such as antiplatelet, anticancer, antifungal, and antiviral properties. In this study, we investigated the effects of a newly-synthesized naphthoquinone derivative, 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone (2-decylamino-DMNQ), on VSMC proliferation and examined the molecular basis of the underlying mechanism. In a dose-dependent manner, 2-decylamino-DMNQ inhibited PDGF-stimulated VSMC proliferation with no apparent cytotoxic effect. While 2-decylamino-DMNQ did not affect PDGF-R{beta} or Akt, it did inhibit the phosphorylation of Erk1/2 and PLC{gamma}1 induced by PDGF. Moreover, 2-decylamino-DMNQ suppressed DNA synthesis through the arrest of cell cycle progression at the G{sub 0}/G{sub 1} phase, including the suppression of pRb phosphorylation and a decrease in PCNA expression, which was related to the downregulation of cell cycle regulatory factors, such as cyclin D1/E and CDK 2/4. It was demonstrated that both U0126, an Erk1/2 inhibitor, and U73122, a PLC{gamma} inhibitor, increased the proportion of cells in the G{sub 0}/G{sub 1} phase of the cell cycle. Thus, these results suggest that 2-decylamino DMNQ has an inhibitory effect on PDGF-induced VSMC proliferation and the mechanism of this action is through cell cycle arrest at the G{sub 0}/G{sub 1} phase. This may be a useful tool for studying interventions for vascular restenosis in coronary

  11. Surface Enhanced Raman Spectroscopic investigations of 2-bromo-3-methylamino-1,4-naphthoquinone on silver nanoparticles.

    PubMed

    Geetha, K; Umadevi, M; Sathe, G V; Vanelle, P; Terme, T; Khoumeri, O

    2015-02-01

    Surface Enhanced Raman Spectroscopic technique has been employed to investigate the orientation of 2-bromo-3-methylamino-1,4-naphthoquinone (BMANQ) on silver nanoparticles. Silver nanoparticles have been prepared by solution combustion method with citric acid as fuel. Silver nanoparticles were characterized by X-ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM) and Scanning Electron Microscopy (SEM). XRD and morphological results confirmed the nanocrystalline nature of the prepared silver nanoparticles. The observed intense CO stretching, CBr stretching and NH2 vibration suggests that the BMANQ molecule may be adsorbed in a 'stand-on' orientation to the silver surface. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy show that charge transfer occurs within the molecule. PMID:25468439

  12. Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity.

    PubMed

    Frenkel-Pinter, Moran; Tal, Sharon; Scherzer-Attali, Roni; Abu-Hussien, Malak; Alyagor, Idan; Eisenbaum, Tal; Gazit, Ehud; Segal, Daniel

    2016-01-01

    Tauopathies, such as Alzheimer's disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo. We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies.

  13. One pot synthesis of poly(5-hydroxyl-1,4-naphthoquinone) stabilized gold nanoparticles using the monomer as the reducing agent for nonenzymatic electrochemical detection of glucose.

    PubMed

    Cooray, M C Dilusha; Liu, Yuping; Langford, Steven J; Bond, Alan M; Zhang, Jie

    2015-01-26

    Monodispersed and highly stable gold nanoparticles with a diameter between 8 and 9 nm were synthesized in a weakly alkaline medium by chemical reduction of AuCl4(-) using 5-hydroxyl-1,4-naphthoquinone, and stabilized by the simultaneously formed poly(hydroxyl-1,4-naphthoquinone). The electrochemical properties of the resultant poly(hydroxyl-1,4-naphthoquinone) stabilized gold nanoparticles (AuNQ NPs) and its electrocatalytic activity for glucose oxidation in alkaline media were then investigated using a range of techniques, including dc cyclic, rotating disk electrode and Fourier transformed large amplitude ac voltammetry. The results demonstrate that these AuNQ NP modified electrodes exhibit excellent catalytic activity toward glucose oxidation in the potential region where the premonolayer oxidation process occurs. The overall catalytic glucose oxidation process was found to be mass transport controlled under the experimental conditions employed, allowing measurements to be conducted with a high reproducibility. The AuNQ NP modified electrodes showed a high sensitivity of 183 μA mM(-1) cm(-2) with a wide linear dynamic range of 0.5-50 mM and a detection limit of 61 μM. However, despite its excellent tolerance toward ascorbic acid, significant interference from uric acid was found with this AuNQ NP modified electrode.

  14. Using of liquid chromatography coupled with diode array detector for determination of naphthoquinones in plants and for investigation of influence of pH of cultivation medium on content of plumbagin in Dionaea muscipula.

    PubMed

    Babula, Petr; Mikelova, Radka; Adam, Vojtech; Kizek, Rene; Havel, Ladislav; Sladky, Zdenek

    2006-09-14

    The interest of many investigators in naphthoquinones is due to their broad-range of biological actions from phytotoxic to fungicidal. The main aim of this work was to investigate the influence of different pH values of cultivation medium on naphthoquinone content in Dionaea muscipula. For this purpose, we optimized the simultaneous analysis of the most commonly occurring naphthoquinones (1,4-naphthoquinone, lawsone, juglone and plumbagin) by high performance liquid chromatography coupled with diode array detector (HPLC-DAD). The most suitable chromatographic conditions were as follows: mobile phase: 0.1 mol l-1 acetic acid:methanol in ratio of 33:67 (%, v/v), flow rate: 0.75 ml min-1 and temperature: 42 degrees C. Moreover, we looked for the most suitable technique for preparation of plant samples (D. muscipula, Juglans regia, Paulownia tomentosa, Impatience glandulifera, Impatience parviflora, Drosera rotundifolia, Drosera spathulata and Drosera capensis) due to their consequent analysis by HPLC-DAD. It clearly follows from the results obtained that sonication were the most suitable technique for preparation of J. regia plants. We also checked the recoveries of the determined naphthoquinones, which were from 96 to 104%. Finally, we investigated the changes in content of plumbagin in D. muscipula plants according to different pH of cultivation medium. The content increased with increasing pH up to 5 and, then, changed gradually. The lower content of plumbagin at lower pH values was of interest to us. Therefore, we determined the content of this naphthoquinone in the cultivation medium, what has not been studied before. We discovered that the lower tissue content of plumbagin was due to secretion of this naphthoquinone into the cultivation medium.

  15. Spectrophotometric determination of procaine hydrochloride in pharmaceutical products using 1,2-naphthoquinone-4-sulfonic acid as the chromogenic reagent

    NASA Astrophysics Data System (ADS)

    Xu, Li Xiao; Shen, Yun Xiu; Wang, Huai You; Jiang, Ji Gang; Xiao, Yan

    2003-11-01

    Spectrophotometric determination of procaine hydrochloride is described. The procaine hydrochloride reacts with 1,2-naphthoquinone-4-sulfonic acid in pH 3.60 buffer solution to form a salmon pink compound, and its maximum absorption wavelength is at 484 nm, ɛ 484=5.22×10 3.The absorbance for procaine hydrochloride from 0.30 to 100 μg ml -1 obeys Beer's law. The linear regression equation of the calibration graph is C=19.23A-0.03, with a linear regression correlative coefficient is 0.9996, the detection limit is 0.28 μg ml -1; recovery is from 98.0 to 105.2%. Effects of pH, surfactant, organic solvent, foreign ions, and standing time on the determination of procaine hydrochloride have been examined. This method is rapid and simple, and can be used for the determination of procaine hydrochloride in injection solution of procaine hydrochloride. The results obtained by this method agreed with those by the official method (dead-stop titration).

  16. Spectrophotometric determination of dapsone in pharmaceutical products using sodium 1,2-naphthoquinone-4-sulfonic as the chromogenic reagent

    NASA Astrophysics Data System (ADS)

    Wang, Huai You; Xu, Li Xiao; Xiao, Yan; Han, Juan

    2004-10-01

    Spectrophotometric determination of dapsone is described. The dapsone reacts with sodium 1,2-naphthoquinone-4-sulfonic in pH 6.98 buffer solution to form a salmon pink compound, and its maximum absorption wavelength is at 525 nm, ɛ525=3.68×10 4 l mol -1 cm -1. The absorbance of dapsone from 0.40 to 10 μg ml -1 obeys Beer's law. The linear regression equation of the calibration graph is C=0.2334 A+0.01288, with a linear regression correlation coefficient of 0.9998, the detection limit is 0.24 μg ml -1, and recovery is from 99.2 to 102.4%. Effects of pH, surfactant, organic solvents, foreign ions, and standing time on the determination of dapsone have been examined. This method is simple and can be used for the determination of dapsone in injection solution of dapsone. The results obtained by this method agreed with those by the official method (dead-stop titration method [The Chinese Pharmacopoeia, Pharmacopoeia Commission, Ministry of Health, vol. 2, fifth ed., PRC Chemical Industry Press, Beijing, 2000, p.720]).

  17. Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new antischistosomal drugs

    PubMed Central

    Johann, Laure; Belorgey, Didier; Huang, Hsin-Hung; Day, Latasha; Chessé, Matthieu; Becker, Katja; Williams, David L.; Davioud-Charvet, Elisabeth

    2016-01-01

    Investigations on the chemistry and mechanism of action of 2-methyl-1,4-naphthoquinone (or menadione) derivatives, revealed 3-phenoxymethyl menadiones as a novel antischistosomal series. These newly synthesized compounds 1–7 and their difluoromethylmenadione counterparts 8–9 were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR) identified as a potential target. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. the glutathione reductase (hGR) and the selenium-dependent human thioredoxin reductase (hTrxR) to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively versus hGR and hTrxR enzymes, in particular those bearing α-fluorophenol methyl ether moieties to improve antischistosomal action. In particular, the (substituted phenoxy)methyl menadione derivative 7 displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox-cycling of SmTGR, and potent antischistosomal action in ex vivo worms. In contrast, the difluoromethylmenadione analogue 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in cultured ex vivo worms. Because none of the compounds tested in vivo was active, a limited bioavailability might compromise compound activity and future studies will be directed toward improving pharmacokinetics properties. PMID:26111549

  18. Synthesis, spectral characterization, molecular structure and pharmacological studies of N'-(1, 4-naphtho-quinone-2yl) isonicotinohyWdrazide

    NASA Astrophysics Data System (ADS)

    Kavitha Rani, P. R.; Fernandez, Annette; George, Annie; Remadevi, V. K.; Sudarsanakumar, M. R.; Laila, Shiny P.; Arif, Muhammed

    2015-01-01

    A simple and efficient procedure was employed for the synthesis of N'-(1,4-naphtho-quinone-2-yl) isonicotinohydrazide (NIH) by the reaction of 2-hydroxy-1,4-naphthaquinone (lawsone) and isonicotinoyl hydrazine in methanol using ultrasonic irradiation. Lawsone is the principal dye, isolated from the leaves of henna (Lawsonia inermis). Structural modification was done on the molecule aiming to get a more active derivative. The structure of the parent compound and the derivative was characterized by elemental analyses, infrared, electronic, 1H, 13C NMR and GC-MS spectra. The fluorescence spectral investigation of the compound was studied in DMSO and ethanol. Single crystal X-ray diffraction studies reveal that NIH crystallizes in monoclinic space group. The DNA cleavage study was monitored by gel electrophoresis method. The synthesized compound was found to have significant antioxidant activity against DPPH radical (IC50 = 58 μM). The in vitro cytotoxic studies of the derivative against two human cancer cell lines MCF-7 (human breast cancer) and HCT-15 (human colon carcinoma cells) using MTT assay revealed that the compound exhibited higher cytotoxic activity with a lower IC50 value indicating its efficiency in killing the cancer cells even at low concentrations. These results suggest that the structural modifications performed on lawsone could be considered a good strategy to obtain a more active drug.

  19. Novel spectrophotometric method for determination of some macrolide antibiotics in pharmaceutical formulations using 1,2-naphthoquinone-4-sulphonate

    NASA Astrophysics Data System (ADS)

    Ashour, Safwan; Bayram, Roula

    2012-12-01

    New, simple and rapid spectrophotometric method has been developed and validated for the assay of two macrolide drugs, azithromycin (AZT) and erythromycin (ERY) in pure and pharmaceutical formulations. The proposed method was based on the reaction of AZT and ERY with sodium 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline medium at 25 °C to form an orange-colored product of maximum absorption peak at 452 nm. All variables were studied to optimize the reaction conditions and the reaction mechanism was postulated. Beer's law was obeyed in the concentration range 1.5-33.0 and 0.92-8.0 μg mL-1 with limit of detection values of 0.026 and 0.063 μg mL-1 for AZT and ERY, respectively. The calculated molar absorptivity values are 4.3 × 104 and 12.3 × 104 L mol-1 cm-1 for AZT and ERY, respectively. The proposed methods were successfully applied to the determination of AZT and ERY in formulations and the results tallied well with the label claim. The results were statistically compared with those of an official method by applying the Student's t-test and F-test. No interference was observed from the concomitant substances normally added to preparations.

  20. Determination of lapachol in the presence of other naphthoquinones using 3MPA-CdTe quantum dots fluorescent probe

    NASA Astrophysics Data System (ADS)

    Aucélio, Ricardo Q.; Peréz-Cordovés, Ana I.; Xavier Lima, Juliano L.; Ferreira, Aurélio Baird B.; Esteva Guas, Ana M.; da Silva, Andrea R.

    3MPA-CdTe QDs in aqueous dispersion was used as a fluorescent probe for the determination of lapachol, a natural naphthoquinone found in plants of the Bignoniaceae family genus Tabebuia. Working QDs dispersions (4.5 × 10-8 mol L-1 of QDs) was prepared in aqueous media containing Tris-HCl buffer pH 7.4 and methanol (10% in volume). The excitation was made at 380 nm with signal measurement at 540 nm. To establish a relationship between fluorescence (corrected to inner filter effect) and concentration of lapachol, a Stern-Volmer model was used. The linear range obtained was from 1.0 × 10-5 to 1.0 × 10-4 mol L-1. The limit of detection (xb - 3 sb) was 8.0 × 10-6 mol L-1. The 3MPA-CdTe QDs probe was tested in the determination of lapachol in urine, previously cleansed in an acrylic polymer. The average recovery was satisfactory.

  1. 1,4-Naphthoquinones and Others NADPH-Dependent Glutathione Reductase-Catalyzed Redox Cyclers as Antimalarial Agents

    PubMed Central

    Belorgey, Didier; Lanfranchi, Don Antoine; Davioud-Charvet, Elisabeth

    2013-01-01

    The homodimeric flavoenzyme glutathione reductase catalyzes NADPH-dependent glutathione disulfide reduction. This reaction is important for keeping the redox homeostasis in human cells and in the human pathogen Plasmodium falciparum. Different types of NADPH-dependent disulfide reductase inhibitors were designed in various chemical series to evaluate the impact of each inhibition mode on the propagation of the parasites. Against malaria parasites in cultures the most potent and specific effects were observed for redox-active agents acting as subversive substrates for both glutathione reductases of the Plasmodium-infected red blood cells. In their oxidized form, these redox-active compounds are reduced by NADPH-dependent flavoenzyme-catalyzed reactions in the cytosol of infected erythrocytes. In their reduced forms, these compounds can reduce molecular oxygen to reactive oxygen species, or reduce oxidants like methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Furthermore, studies on a fluorinated suicide-substrate of the human glutathione reductase indicate that the glutathione reductase-catalyzed bioactivation of 3-benzylnaphthoquinones to the corresponding reduced 3-benzoyl metabolites is essential for the observed antimalarial activity. In conclusion, the antimalarial lead naphthoquinones are suggested to perturb the major redox equilibria of the targeted cells. These effects result in development arrest of the parasite and contribute to the removal of the parasitized erythrocytes by macrophages. PMID:23116403

  2. Modulatory Effect of 2-(4-Hydroxyphenyl)amino-1,4-naphthoquinone on Endothelial Vasodilation in Rat Aorta

    PubMed Central

    Palacios, Javier; Cifuentes, Fredi; Valderrama, Jaime A.; Benites, Julio; Ríos, David; González, Constanza; Cartes-Saavedra, Benjamín; Wyneken, Ursula; González, Pamela; Owen, Gareth I.; Pardo, Fabián; Sobrevia, Luis

    2016-01-01

    The vascular endothelium plays an essential role in the control of the blood flow. Pharmacological agents like quinone (menadione) at various doses modulate this process in a variety of ways. In this study, Q7, a 2-phenylamino-1,4-naphthoquinone derivative, significantly increased oxidative stress and induced vascular dysfunction at concentrations that were not cytotoxic to endothelial or vascular smooth muscle cells. Q7 reduced nitric oxide (NO) levels and endothelial vasodilation to acetylcholine in rat aorta. It also blunted the calcium release from intracellular stores by increasing the phenylephrine-induced vasoconstriction when CaCl2 was added to a calcium-free medium but did not affect the influx of calcium from extracellular space. Q7 increased the vasoconstriction to BaCl2 (10−3 M), an inward rectifying K+ channels blocker, and blocked the vasodilation to KCl (10−2 M) in aortic rings precontracted with BaCl2. This was recovered with sodium nitroprusside (10−8 M), a NO donor. In conclusion, Q7 induced vasoconstriction was through a modulation of cellular mechanisms involving calcium fluxes through K+ channels, and oxidative stress induced endothelium damage. These findings contribute to the characterization of new quinone derivatives with low cytotoxicity able to pharmacologically modulate vasodilation.

  3. New insights into 3-(aminomethyl)naphthoquinones: Evaluation of cytotoxicity, electrochemical behavior and search for structure-activity correlation.

    PubMed

    da Silva, Gustavo B; Neves, Amanda P; Vargas, Maria D; Marinho-Filho, José D B; Costa-Lotufo, Letícia V

    2016-08-01

    Herein we describe the structure-activity relationship of a large library of Mannich bases (MBs) synthesized from 2-hydroxy-1,4-naphthoquinone. In general, the compounds have shown high to moderate activity against the HL-60 (promyelocytic leukaemia) cell line with IC50=1.1-19.2μM. Our results suggest that the nature of the aryl moiety introduced in the structure of MBs by the aldehyde component is crucial to the cytotoxicity, and although the group originated from the primary amine has a lesser influence, aromatic ones were found to suppress the activity. Thus, MBs derived from salicylaldehydes or 2-pyridinecarboxaldehyde and aliphatic amines are the most active compounds. A satisfactory correlation of the EpIIc versus IC50 (μM) in dimethylsulfoxide was observed. The most cytotoxic MBs (Series a-c, derived from salicylaldehydes) showed the least negative EpIIc values. Noteworthy, however, Series d (derived from 2-pyridinecarboxaldehyde) did not follow this correlation. They exhibited both the lowest IC50 and the most negative EpIIc values, thus suggesting that other factors also influence the cytotoxicity of the MBs, such as lipophilicity, electronic distribution and hydrogen bonding. PMID:27363939

  4. Modulatory Effect of 2-(4-Hydroxyphenyl)amino-1,4-naphthoquinone on Endothelial Vasodilation in Rat Aorta

    PubMed Central

    Palacios, Javier; Cifuentes, Fredi; Valderrama, Jaime A.; Benites, Julio; Ríos, David; González, Constanza; Cartes-Saavedra, Benjamín; Wyneken, Ursula; González, Pamela; Owen, Gareth I.; Pardo, Fabián; Sobrevia, Luis

    2016-01-01

    The vascular endothelium plays an essential role in the control of the blood flow. Pharmacological agents like quinone (menadione) at various doses modulate this process in a variety of ways. In this study, Q7, a 2-phenylamino-1,4-naphthoquinone derivative, significantly increased oxidative stress and induced vascular dysfunction at concentrations that were not cytotoxic to endothelial or vascular smooth muscle cells. Q7 reduced nitric oxide (NO) levels and endothelial vasodilation to acetylcholine in rat aorta. It also blunted the calcium release from intracellular stores by increasing the phenylephrine-induced vasoconstriction when CaCl2 was added to a calcium-free medium but did not affect the influx of calcium from extracellular space. Q7 increased the vasoconstriction to BaCl2 (10−3 M), an inward rectifying K+ channels blocker, and blocked the vasodilation to KCl (10−2 M) in aortic rings precontracted with BaCl2. This was recovered with sodium nitroprusside (10−8 M), a NO donor. In conclusion, Q7 induced vasoconstriction was through a modulation of cellular mechanisms involving calcium fluxes through K+ channels, and oxidative stress induced endothelium damage. These findings contribute to the characterization of new quinone derivatives with low cytotoxicity able to pharmacologically modulate vasodilation. PMID:27672420

  5. 1,2-Naphthoquinone activates vanilloid receptor 1 through increased protein tyrosine phosphorylation, leading to contraction of guinea pig trachea

    SciTech Connect

    Kikuno, Shota; Taguchi, Keiko; Iwamoto, Noriko; Yamano, Shigeru; Cho, Arthur K.; Froines, John R.; Kumagai, Yoshito . E-mail: yk-em-tu@md.tsukuba.ac.jp

    2006-01-15

    1,2-Naphthoquinone (1,2-NQ) has recently been identified as an environmental quinone in diesel exhaust particles (DEP) and atmospheric PM{sub 2.5}. We have found that this quinone is capable of causing a concentration-dependent contraction of tracheal smooth muscle in guinea pigs with EC{sub 5} value of 18.7 {mu}M. The contraction required extracellular calcium and was suppressed by L-type calcium channel blockers nifedipine and diltiazem. It was found that 1,2-NQ activated phospholipase A2 (PLA2)/lipoxygenase (LO)/vanilloid receptor (VR1) signaling. Additionally, 1,2-NQ was capable of transactivating protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (EGFR) in guinea pig trachea, suggesting that phosphorylation of PTKs contributes to 1,2-NQ-induced tracheal contraction. Consistent with this notion, this action was blocked by the PTKs inhibitor genistein and the EGFR antagonist PD153035, indicating that contraction was, at least in part, attributable to PTKs phosphorylation that activates VR1, resulting in increased intracellular calcium content in the smooth muscle cells.

  6. Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships

    PubMed Central

    Schmidt, Thomas J.; Borborema, Samanta E. T.; Ferreira, Vitor F.; Rocha, David R.; Tempone, Andre G.

    2014-01-01

    Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis. PMID:25171058

  7. o-Iodoxybenzoic Acid-Initiated One-Pot Synthesis of 4-Arylthio-1,2-naphthoquinones, 4-Arylthio-1,2-diacetoxynaphthalenes, and 5-Arylthio-/5-Aminobenzo[a]phenazines.

    PubMed

    Mishra, Abhaya Kumar; Moorthy, Jarugu Narasimha

    2016-08-01

    1,2-Naphthoquiones and their derivatives constitute an important category of compounds of relevance in pharmaceutical and material chemistry. It is shown that 1,2-naphthoquinones generated by o-iodoxybenzoic acid-mediated oxidation of 2-naphthols can be subjected to a cascade of reactions, namely oxidation, Michael addition, reduction, acetylation, and cyclocondensation, in the same pot to afford diverse 4-arylthio-1,2-naphthoquinones 2, 4-arylthio-1,2-diacetoxynaphthalenes 3, and 5-arylthio-/5-aminobenzo[a]phenazines 4 in very good isolated yields. The multistep single-pot synthesis occurs smoothly in DMF at rt.

  8. Identification and localization of bioactive naphthoquinones in the roots and rhizosphere of Paterson's curse (Echium plantagineum), a noxious invader.

    PubMed

    Zhu, Xiaocheng; Skoneczny, Dominik; Weidenhamer, Jeffrey D; Mwendwa, James M; Weston, Paul A; Gurr, Geoff M; Callaway, Ragan M; Weston, Leslie A

    2016-06-01

    Bioactive plant secondary products are frequently the drivers of complex rhizosphere interactions, including those with other plants, herbivores and microbiota. These chemically diverse molecules typically accumulate in a highly regulated manner in specialized plant tissues and organelles. We studied the production and localization of bioactive naphthoquinones (NQs) in the roots of Echium plantagineum, an invasive endemic weed in Australia. Roots of E. plantagineum produced red-coloured NQs in the periderm of primary and secondary roots, while seedling root hairs exuded NQs in copious quantities. Confocal imaging and microspectrofluorimetry confirmed that bioactive NQs were deposited in the outer layer of periderm cells in mature roots, resulting in red colouration. Intracellular examination revealed that periderm cells contained numerous small red vesicles for storage and intracellular transport of shikonins, followed by subsequent extracellular deposition. Periderm and root hair extracts of field- and phytotron-grown plants were analysed by UHPLC/Q-ToF MS (ultra high pressure liquid chromatography coupled to quadrupole time of flight mass spectrometry) and contained more than nine individual NQs, with dimethylacrylshikonin, and phytotoxic shikonin, deoxyshikonin and acetylshikonin predominating. In seedlings, shikonins were first found 48h following germination in the root-hypocotyl junction, as well as in root hair exudates. In contrast, the root cortices of both seedling and mature root tissues were devoid of NQs. SPRE (solid phase root zone extraction) microprobes strategically placed in soil surrounding living E. plantagineum plants successfully extracted significant levels of bioactive shikonins from living roots, rhizosphere and bulk soil surrounding roots. These findings suggest important roles for accumulation of shikonins in the root periderm and subsequent rhizodeposition in plant defence, interference, and invasion success. PMID:27194735

  9. CHNQ, a novel 2-Chloro-1,4-naphthoquinone derivative of quercetin, induces oxidative stress and autophagy both in vitro and in vivo.

    PubMed

    Enayat, Shabnam; Şeyma Ceyhan, M; Taşkoparan, Betül; Stefek, Milan; Banerjee, Sreeparna

    2016-04-15

    Quercetin (Qc) shows strong antitumor effects but has limited clinical application due to poor water solubility and bioavailability. In a screening of novel semi-synthetic derivatives of Qc, 3,7-dihydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxyphenyl]-5-hydroxychromen-4-one (CHNQ) could ameliorate acetic acid induced acute colitis in vivo more efficiently than Qc. Since inflammation contributes to colorectal cancer (CRC), we have hypothesized that CHNQ may have anti-cancer effects. Using CRC cell lines HCT-116 and HT-29, we report that CHNQ was three-fold more cytotoxic than Qc along with a robust induction of apoptosis. As expected from naphthoquinones such as CHNQ, a strong induction of oxidative stress was observed. This was accompanied by reactive oxygen species (ROS) induced autophagy marked by a dramatic increase in the lipidation of LC3, decreased activation of Akt/PKB, acidic vesicle accumulation and puncta formation in HCT-116 cells treated with CHNQ. Interestingly, an incomplete autophagy was observed in HT-29 cells where CHNQ treatment led to LC3 lipidation, but not the formation of acidic vacuoles. CHNQ-induced cytotoxicity, ROS formation and autophagy were also detected in vivo in Saccharomyces cerevisiae strain RDKY3615 (WinstonS288C background). Overall, we propose that CHNQ can induce cancer cell death through the induction of oxidative stress, and may be examined further as a potential chemotherapeutic drug. PMID:26946942

  10. An assessment of the genotoxicity of 2-hydroxy-1,4-naphthoquinone, the natural dye ingredient of Henna.

    PubMed

    Kirkland, David; Marzin, Daniel

    2003-06-01

    2-Hydroxy-1,4-naphthoquinone (HNQ; Lawsone; CAS 83-72-7) is the principal natural dye ingredient contained in the leaves of Henna (Lawsonia inermis). Published genotoxicity studies on HNQ suggested it was a weak bacterial mutagen for Salmonella typhimurium strain TA98 or was more clearly mutagenic for strain TA 2637, both in the presence of metabolic activation. HNQ was unable to induce sex-linked recessive lethal mutations in Drosophila melanogaster. However, a small increase in micronucleus frequency was reported in the bone marrow of mice at a single mid-range dose level, 24h after intraperitoneal injection. In view of the wide use of Henna hair dyes it was deemed necessary to conduct a thorough investigation, under Good Laboratory Practice conditions, of the genotoxicity of HNQ. HNQ was non-mutagenic in bacterial (Ames test) or mammalian (V79 hprt) assays. It was borderline positive in a mouse lymphoma tk mutation assay and a chromosome aberration test (CHO cells), results that may reflect a similar clastogenic mechanism. Negative in vivo genotoxicity results were noted in the rat hepatocyte in vivo/in vitro UDS test, in peripheral lymphocytes (chromosome aberrations) of rats receiving repeated oral doses of HNQ at the MTD for 28 days, and in mouse and hamster bone marrow chromosome aberration tests. However small, but statistically significant increases in the incidence of bone marrow micronuclei were observed in two out of five tests at 72 h after dosing, but not at 24 or 48 h. There was evidence of haematotoxicity at 72 h, which may have been enhanced by the vehicle (DMSO) used in the positive tests. As erythropoiesis and administration of haematotoxic agents are known to induce small increases in the frequency of bone marrow micronuclei, typically at delayed sampling times, the data suggest that the positive 72 h response produced by HNQ is consistent with stimulation of haematopoiesis subsequent to haematological toxicity of HNQ, and not due to a DNA

  11. An assessment of the genotoxicity of 2-hydroxy-1,4-naphthoquinone, the natural dye ingredient of Henna.

    PubMed

    Kirkland, David; Marzin, Daniel

    2003-06-01

    2-Hydroxy-1,4-naphthoquinone (HNQ; Lawsone; CAS 83-72-7) is the principal natural dye ingredient contained in the leaves of Henna (Lawsonia inermis). Published genotoxicity studies on HNQ suggested it was a weak bacterial mutagen for Salmonella typhimurium strain TA98 or was more clearly mutagenic for strain TA 2637, both in the presence of metabolic activation. HNQ was unable to induce sex-linked recessive lethal mutations in Drosophila melanogaster. However, a small increase in micronucleus frequency was reported in the bone marrow of mice at a single mid-range dose level, 24h after intraperitoneal injection. In view of the wide use of Henna hair dyes it was deemed necessary to conduct a thorough investigation, under Good Laboratory Practice conditions, of the genotoxicity of HNQ. HNQ was non-mutagenic in bacterial (Ames test) or mammalian (V79 hprt) assays. It was borderline positive in a mouse lymphoma tk mutation assay and a chromosome aberration test (CHO cells), results that may reflect a similar clastogenic mechanism. Negative in vivo genotoxicity results were noted in the rat hepatocyte in vivo/in vitro UDS test, in peripheral lymphocytes (chromosome aberrations) of rats receiving repeated oral doses of HNQ at the MTD for 28 days, and in mouse and hamster bone marrow chromosome aberration tests. However small, but statistically significant increases in the incidence of bone marrow micronuclei were observed in two out of five tests at 72 h after dosing, but not at 24 or 48 h. There was evidence of haematotoxicity at 72 h, which may have been enhanced by the vehicle (DMSO) used in the positive tests. As erythropoiesis and administration of haematotoxic agents are known to induce small increases in the frequency of bone marrow micronuclei, typically at delayed sampling times, the data suggest that the positive 72 h response produced by HNQ is consistent with stimulation of haematopoiesis subsequent to haematological toxicity of HNQ, and not due to a DNA

  12. The effect of Na+ and K+ doping on the properties of sol-gel deposited 2-hydroxy-1,4-naphthoquinone thin films

    NASA Astrophysics Data System (ADS)

    Al-Omari, Mahmoud; Sel, Kivanc; Mueller, Anja; Mellinger, Axel; Kaya, Tolga

    2013-05-01

    We describe the use of 2-hydroxy-1,4-naphthoquinone (HNQ) thin films as a potential water vapor and electrolyte sensing material towards the goal of non-invasive relative humidity and sweat detection. We have successfully made HNQ sol-gel thin films and studied the effects of sodium and potassium ions on their optical and electrical characteristics. Ultraviolet-visible absorbance and Fourier transform infrared spectroscopy measurements along with scanning electron microscopy demonstrated that we were able to dope HNQ thin films with Na+ and K+ ions, which are the main electrolyte contents in sweat. While the conductivity of thin films increased by at least an order of magnitude, energy band gaps decreased by doping HNQ with Na+ and K+ ions. Relative humidity test results showed that HNQ-based thin-films can be used as a sensing material for water vapor. Room temperature current-voltage measurements were also performed to determine the surface conductivity.

  13. Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives.

    PubMed

    Ogindo, Charles O; Khraiwesh, Mozna H; George, Matthew; Brandy, Yakini; Brandy, Nailah; Gugssa, Ayele; Ashraf, Mohammad; Abbas, Muneer; Southerland, William M; Lee, Clarence M; Bakare, Oladapo; Fang, Yayin

    2016-08-15

    Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson's r value of 0.88 (P value <0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r=0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease. PMID:27345756

  14. Furano-1,2-naphthoquinone inhibits EGFR signaling associated with G2/M cell cycle arrest and apoptosis in A549 cells.

    PubMed

    Su, J C; Lin, K L; Chien, C M; Tseng, C H; Chen, Y L; Chang, L S; Lin, S R

    2010-12-01

    Furano-1,2-naphthoquinone (FNQ), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exhibits an anti-carcinogenic effect. FNQ exerted anti-proliferative activity with the G(2)/M cell cycle arrest and apoptosis in A549 cells. FNQ-induced G(2)/M arrest was correlated with a marked decrease in the expression levels of cyclin A and cyclin B, and their activating partner cyclin-dependent kinases (Cdk) 1 and 2 with concomitant induction of p53, p21, and p27. FNQ-induced apoptosis was accompanied with Bax up-regulation and the down-regulation of Bcl-2, X-linked inhibitor of apoptosis (XIAP), and survivin, resulting in cytochrome c release and sequential activation of caspase-9 and caspase-3. Western blot analysis revealed that FNQ suppressed EGFR phosphorylation and JAK2, STAT3, and STAT5 activation, but increased in activation of p38 MAPK and c-Jun NH2-terminal kinase (JNK) stress signal. The combined treatment of FNQ with AG1478 (a specific EGFR inhibitor) significantly enhanced the G(2)/M arrest and apoptosis, and also led to up-regulation in Bax, p53, p21, p27, release of mitochondrial cytochrome c, and down-regulation of Bcl-2, XIAP, survivin, cyclin A, cyclin B, Cdk1, and Cdk2 in A549 cells. These findings suggest that FNQ-mediated cytotoxicity of A549 cell related with the G(2)/M cell cycle arrest and apoptosis via inactivation of EGFR-mediated signaling pathway. PMID:21104938

  15. Novel drug design for Chagas disease via targeting Trypanosoma cruzi tubulin: Homology modeling and binding pocket prediction on Trypanosoma cruzi tubulin polymerization inhibition by naphthoquinone derivatives.

    PubMed

    Ogindo, Charles O; Khraiwesh, Mozna H; George, Matthew; Brandy, Yakini; Brandy, Nailah; Gugssa, Ayele; Ashraf, Mohammad; Abbas, Muneer; Southerland, William M; Lee, Clarence M; Bakare, Oladapo; Fang, Yayin

    2016-08-15

    Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson's r value of 0.88 (P value <0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r=0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease.

  16. Synthesis and characterization of n-alkylamino derivatives of vitamin K3: Molecular structure of 2-propylamino-3-methyl-1,4-naphthoquinone and antibacterial activities

    NASA Astrophysics Data System (ADS)

    Chadar, Dattatray; Camilles, Maria; Patil, Rishikesh; Khan, Ayesha; Weyhermüller, Thomas; Salunke-Gawali, Sunita

    2015-04-01

    We would like to introduce eight analogues of n-alkylamino derivatives of vitamin K3 (2-methyl-1,4-naphthoquinone) viz, 2-(n-alkylamino)-3-methyl-1,4-naphthoquinone (where n-alkyl is methyl; LM-1, ethyl; LM-2, propyl; LM-3, butyl; LM-4, pentyl; LM-5, hexyl; LM-6, heptyl; LM-7, octyl; LM-8). All the above analogues have been successfully synthesized from vitamin K3 and characterized using different analytical techniques. Furthermore, in order to understand the mechanistic aspects of formation of LM-1 to LM-8 compounds, we could propose the mechanism. The FT-IR analysis of LM-1 to LM-8 indicate the presence of characteristic band of Nsbnd H group ∼3287-3364 cm-1, the variation was attributed to extensive intramolecular hydrogen bonding interaction. The molecular structure of LM-3 compound has been confirmed by single crystal X-ray diffraction analysis. LM-3 compound crystallises in triclinic space group P1. There were four independent molecules in asymmetric unit cell and their molecular interactions observed via Nsbnd H⋯O, Csbnd H⋯O and π-π stacking of quinonoid rings. Pharmacological potential of all compounds has been evaluated in terms of their antibacterial activities against Pseudomonas aeruginosa and Staphylococcus aureus. All the compounds were active against both the strains while LM-2 was found to be more effective with a minimum inhibition concentration of 0.3125 μg/mL and 0.156 μg/mL respectively.

  17. Hydroxylated Dimeric Naphthoquinones Increase the Generation of Reactive Oxygen Species, Induce Apoptosis of Acute Myeloid Leukemia Cells and Are Not Substrates of the Multidrug Resistance Proteins ABCB1 and ABCG2

    PubMed Central

    Lapidus, Rena G.; Carter-Cooper, Brandon A.; Sadowska, Mariola; Choi, Eun Yong; Wonodi, Omasiri; Muvarak, Nidal; Natarajan, Karthika; Pidugu, Lakshmi S.; Jaiswal, Anil; Toth, Eric A.; Rassool, Feyruz V.; Etemadi, Arash; Sausville, Edward A.; Baer, Maria R.; Emadi, Ashkan

    2016-01-01

    Selective targeting of the oxidative state, which is a tightly balanced fundamental cellular property, is an attractive strategy for developing novel anti-leukemic chemotherapeutics with potential applications in the treatment of acute myeloid leukemia (AML), a molecularly heterogeneous disease. Dimeric naphthoquinones (BiQs) with the ability to undergo redox cycling and to generate reactive oxygen species (ROS) in cancer cells are a novel class of compounds with unique characteristics that make them excellent candidates to be tested against AML cells. We evaluated the effect of two BiQ analogues and one monomeric naphthoquinone in AML cell lines and primary cells from patients. All compounds possess one halogen and one hydroxyl group on the quinone cores. Dimeric, but not monomeric, naphthoquinones demonstrated significant anti-AML activity in the cell lines and primary cells from patients with favorable therapeutic index compared to normal hematopoietic cells. BiQ-1 effectively inhibited clonogenicity and induced apoptosis as measured by Western blotting and Annexin V staining and mitochondrial membrane depolarization by flow cytometry. BiQ-1 significantly enhances intracellular ROS levels in AML cells and upregulates expression of key anti-oxidant protein, Nrf2. Notably, systemic exposure to BiQ-1 was well tolerated in mice. In conclusion, we propose that BiQ-induced therapeutic augmentation of ROS in AML cells with dysregulation of antioxidants kill leukemic cells while normal cells remain relatively intact. Further studies are warranted to better understand this class of potential chemotherapeutics. PMID:26797621

  18. Determination of biogenic amines in wines by ion-pair liquid chromatography and post-column derivatization with 1,2-naphthoquinone-4-sulphonate.

    PubMed

    Hlabangana, Leah; Hernández-Cassou, Santiago; Saurina, Javier

    2006-10-13

    A liquid chromatographic method with post-column derivatization for the determination of biogenic amines in wines is proposed. The method is based on the separation of amines by ion-pair chromatography using sodium heptanesulfonate (SHS) and on-line labeling of analytes with 1,2-naphthoquinone-4-sulfonate. The principal factors influencing the separation (acetonitrile and SHS concentration) have been considered for the optimization of the elution gradient through factorial design and multicriteria decision-making. Figures of merit have been established using red wine samples. Detection limits range from 0.2 to 3 mg L(-1), the peak area run-to-run repeatability from 1.6 to 4.6% and the retention time repeatability lower than 1.2%. Recoveries ranging from 92 and 108% prove the accuracy of the method for determining ethanolamine, ethylamine, histamine and tyramine in commercial red wines. The proposed method has been applied to the analysis of wines from different Spanish regions.

  19. Furano-1,2-Naphthoquinone Inhibits Src and PI3K/Akt Signaling Pathways in Ca9-22 Human Oral Squamous Carcinoma Cells.

    PubMed

    Lin, Kuei-Li; Chien, Ching-Ming; Tseng, Chih-Hua; Chen, Yeh-Long; Chang, Long-Sen; Lin, Shinne-Ren

    2014-05-01

    Furano-1,2-naphthoquinone (FNQ), a biologically active component ofAvicennia marina, has been demonstrated to display anticancer activity. FNQ exerted cytotoxicity with the G2/M cell cycle arrest and apoptosis in Ca9-22 cells. FNQ-induced G2/M arrest was correlated with a marked decrease in the expression levels of cyclin A and cyclin B, and their activating partner cyclin-dependent kinases (CDK) 1 and 2 with concomitant induction of p27. FNQ-induced apoptosis was accompanied by Bax and Bad upregulation, and the downregulation of Bcl-2, Bcl-XL, Mcl-1, and X-linked inhibitor of apoptosis (XIAP), resulting in cytochrome C release and sequential activation of caspase-9 and caspase-3. Mechanistic studies showed that FNQ suppressed Src phosphorylation, PI3K, and Akt activation in Ca9-22 cells. Moreover, the Src inhibitor PP2 reduced the phosphorylation of Src and activation of PI3K/Akt, which was comparable with FNQ treatment. The combined treatment of FNQ with PP2 enhanced the cell cycle arrest and apoptosis and also led to the downregulation of Bcl-XL, Mcl-1, XIAP, cyclin A, cyclin B, CDK1, and CDK2 and upregulation of p27, Bax, and Bad. These findings suggest that FNQ-mediated cytotoxicity of Ca9-22 cells is related with the G2/M cell cycle arrest and apoptosis via inactivation of Src and PI3K/Akt-mediated signaling pathways. PMID:22505597

  20. 2-Methoxy-6-acetyl-7-methyljuglone (MAM), a natural naphthoquinone, induces NO-dependent apoptosis and necroptosis by H2O2-dependent JNK activation in cancer cells.

    PubMed

    Sun, Wen; Bao, Jiaolin; Lin, Wei; Gao, Hongwei; Zhao, Wenwen; Zhang, Qingwen; Leung, Chung-Hang; Ma, Dik-Lung; Lu, Jinjian; Chen, Xiuping

    2016-03-01

    Redox signaling plays a fundamental role in maintaining cell physiological activities. A deregulation of this balance through oxidative stress or nitrosative stress has been implicated in cancer. Here, we reported that 2-methoxy-6-acetyl-7-methyl juglone (MAM), a natural naphthoquinone isolated from Polygonum cuspidatum Sieb. et Zucc, caused hydrogen peroxide (H2O2) dependent activation of JNK and induced the expression of inducible nitric oxide synthase (iNOS), thereby leading to nitric oxide (NO) generation in multiple cancer cells. Nitrosative stress induced necroptosis in A549 lung cancer cells, but resulted in caspase-dependent intrinsic apoptosis in B16-F10 melanoma and MCF7 breast cancer cells. In addition, a decrease in GSH/GSSG levels accompanied with increased ROS production was observed. Reversal of ROS generation and cell death in GSH pretreated cells indicated the involvement of GSH depletion in MAM mediated cytotoxicity. In summary, a natural product MAM induced NO-dependent multiple forms of cell death in cancer cells mediated by H2O2-dependent JNK activation in cancer cells. GSH depletion might play an initial role in MAM-induced cytotoxicity. PMID:26802903

  1. Inhibitory effects of LPA1 on cell motile activities stimulated by hydrogen peroxide and 2,3-dimethoxy-1,4-naphthoquinone in fibroblast 3T3 cells.

    PubMed

    Hirane, Miku; Araki, Mutsumi; Dong, Yan; Honoki, Kanya; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

    2013-11-01

    Reactive oxygen species (ROS) are known to mediate a variety of biological responses, including cell motility. Recently, we indicated that lysophosphatidic acid (LPA) receptor-3 (LPA3) increased cell motile activity stimulated by hydrogen peroxide. In the present study, we assessed the role of LPA1 in the cell motile activity mediated by ROS in mouse fibroblast 3T3 cells. 3T3 cells were treated with hydrogen peroxide and 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) at concentrations of 0.1 and 1 μM for 48 h. In cell motility assays with Cell Culture Inserts, the cell motile activities of 3T3 cells treated with hydrogen peroxide and DMNQ were significantly higher than those of untreated cells. 3T3 cells treated with hydrogen peroxide and DMNQ showed elevated expression levels of the Lpar3 gene, but not the Lpar1 and Lpar2 genes. To investigate the effects of LPA1 on the cell motile activity induced by hydrogen peroxide and DMNQ, Lpar1-overexpressing (3T3-a1) cells were generated from 3T3 cells and treated with hydrogen peroxide and DMNQ. The cell motile activities stimulated by hydrogen peroxide and DMNQ were markedly suppressed in 3T3-a1 cells. These results suggest that LPA signaling via LPA1 inhibits the cell motile activities stimulated by hydrogen peroxide and DMNQ in 3T3 cells.

  2. Validated spectrophotometric method for the determination, spectroscopic characterization and thermal structural analysis of duloxetine with 1,2-naphthoquinone-4-sulphonate

    NASA Astrophysics Data System (ADS)

    Ulu, Sevgi Tatar; Elmali, Fikriye Tuncel

    2012-03-01

    A novel, selective, sensitive and simple spectrophotometric method was developed and validated for the determination of the antidepressant duloxetine hydrochloride in pharmaceutical preparation. The method was based on the reaction of duloxetine hydrochloride with 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline media to yield orange colored product. The formation of this complex was also confirmed by UV-visible, FTIR, 1H NMR, Mass spectra techniques and thermal analysis. This method was validated for various parameters according to ICH guidelines. Beer's law is obeyed in a range of 5.0-60 μg/mL at the maximum absorption wavelength of 480 nm. The detection limit is 0.99 μg/mL and the recovery rate is in a range of 98.10-99.57%. The proposed methods was validated and applied to the determination of duloxetine hydrochloride in pharmaceutical preparation. The results were statistically analyzed and compared to those of a reference UV spectrophotometric method.

  3. Copper(II)-catalyzed sequential C,N-difunctionalization of 1,4-naphthoquinone for the synthesis of benzo[f]indole-4,9-diones under base-free condition.

    PubMed

    Sun, Jin-Wei; Wang, Xiang-Shan; Liu, Yun

    2013-10-18

    An efficient synthesis of benzo[f]indole-4,9-diones has been achieved by copper(II)-catalyzed naphthoquinone sequential C,N-difunctionalization reactions with β-enaminones. New C-C and C-N bonds are easily formed in the reaction course. Copper(II) salt plays a dual role as Lewis acid and oxidative catalyst, and O2 acts as the terminal oxidant. The advantage of this reaction is the high atom economy with broad substrate scope and excellent yields. The reaction can be scaled up to using at least grams of substrates. PMID:24070011

  4. Identification and localization of bioactive naphthoquinones in the roots and rhizosphere of Paterson’s curse (Echium plantagineum), a noxious invader

    PubMed Central

    Zhu, Xiaocheng; Skoneczny, Dominik; Weidenhamer, Jeffrey D.; Mwendwa, James M.; Weston, Paul A.; Gurr, Geoff M.; Callaway, Ragan M.; Weston, Leslie A.

    2016-01-01

    Bioactive plant secondary products are frequently the drivers of complex rhizosphere interactions, including those with other plants, herbivores and microbiota. These chemically diverse molecules typically accumulate in a highly regulated manner in specialized plant tissues and organelles. We studied the production and localization of bioactive naphthoquinones (NQs) in the roots of Echium plantagineum, an invasive endemic weed in Australia. Roots of E. plantagineum produced red-coloured NQs in the periderm of primary and secondary roots, while seedling root hairs exuded NQs in copious quantities. Confocal imaging and microspectrofluorimetry confirmed that bioactive NQs were deposited in the outer layer of periderm cells in mature roots, resulting in red colouration. Intracellular examination revealed that periderm cells contained numerous small red vesicles for storage and intracellular transport of shikonins, followed by subsequent extracellular deposition. Periderm and root hair extracts of field- and phytotron-grown plants were analysed by UHPLC/Q-ToF MS (ultra high pressure liquid chromatography coupled to quadrupole time of flight mass spectrometry) and contained more than nine individual NQs, with dimethylacrylshikonin, and phytotoxic shikonin, deoxyshikonin and acetylshikonin predominating. In seedlings, shikonins were first found 48h following germination in the root-hypocotyl junction, as well as in root hair exudates. In contrast, the root cortices of both seedling and mature root tissues were devoid of NQs. SPRE (solid phase root zone extraction) microprobes strategically placed in soil surrounding living E. plantagineum plants successfully extracted significant levels of bioactive shikonins from living roots, rhizosphere and bulk soil surrounding roots. These findings suggest important roles for accumulation of shikonins in the root periderm and subsequent rhizodeposition in plant defence, interference, and invasion success. PMID:27194735

  5. Ferrocene and (arene)ruthenium(II) complexes of the natural anticancer naphthoquinone plumbagin with enhanced efficacy against resistant cancer cells and a genuine mode of action.

    PubMed

    Spoerlein-Guettler, Cornelia; Mahal, Katharina; Schobert, Rainer; Biersack, Bernhard

    2014-09-01

    A series of ferrocene and (arene)ruthenium(II) complexes attached to the naturally occurring anticancer naphthoquinones plumbagin and juglone was tested for efficacy against various cancer cell lines and for alterations in the mode of action. The plumbagin ferrocene and (p-cymene)Ru(II) conjugates 1c and 2a overcame the multi-drug drug resistance of KB-V1/Vbl cervix carcinoma cells and showed IC50 (72 h) values around 1 μM in growth inhibition assays using 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT). They were further investigated for their influence on the cell cycle of KB-V1/Vbl and HCT-116 colon carcinoma cells, on the generation of reactive oxygen species (ROS) by the latter cell line, for their substrate character for the P-glycoprotein drug eflux pump via the calcein-AM efflux assays, and for DNA affinity by the electrophoretic mobility shift assay (EMSA). The derivatives 1c and 2a increased the number of dead cancer cells (sub-G0/G1 fraction) in a dose- and time-dependent manner. ROS levels were significantly increased upon treatment with 1c and 2a. These compounds also showed a greater affinity to linear DNA than plumbagin. While plumbagin did not affect calcein-AM transport by P-glycoprotein the derivatives 1c and 2a exhibited a 50% or 80% inhibition of the P-glycoprotein-mediated calcein-AM efflux relative to the clinically established sensitizer verapamil.

  6. Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new anti-schistosomal drugs.

    PubMed

    Johann, Laure; Belorgey, Didier; Huang, Hsin-Hung; Day, Latasha; Chessé, Matthieu; Becker, Katja; Williams, David L; Davioud-Charvet, Elisabeth

    2015-08-01

    Investigations regarding the chemistry and mechanism of action of 2-methyl-1,4-naphthoquinone (or menadione) derivatives revealed 3-phenoxymethyl menadiones as a novel anti-schistosomal chemical series. These newly synthesized compounds (1-7) and their difluoromethylmenadione counterparts (8, 9) were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR), which has been identified as a potential target for anti-schistosomal drugs. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. glutathione reductase (hGR) and selenium-dependent human thioredoxin reductase (hTrxR), to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively compared to hGR and hTrxR enzymes, in particular those bearing an α-fluorophenol methyl ether moiety, which improves anti-schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (7) displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox cycling of SmTGR, and potent anti-schistosomal action in worms cultured ex vivo. In contrast, the difluoromethylmenadione analog 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in worms cultured ex vivo. Despite ex vivo activity, none of the compounds tested was active in vivo, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability.

  7. Interactions of formate ion with triplets of anthraquinone-2-sulfonate, 1,4-naphthoquinone, benzophenone-4-carboxylate, and benzophenone-4-sulfonate

    SciTech Connect

    Loeff, I.; Goldstein, S.; Treinin, A. ); Linschitz, H. )

    1991-05-30

    The interaction of formate with the triplet states of naphthoquinone (NQ), anthraquinone-2-sulfonate (AQS), benzophenone-4-carboxylate (BC), and benzophenone-4-sulfonate (BS) was studied by laser flash photolysis. Rate constants were determined either by direct measurement of triplet lifetimes or by inhibition of product yields by competitive reactants. Radical products are formed in two stages, direct reduction by formate and efficient secondary reduction by initially formed CO{sub 2}{sup {sm bullet}{minus}} radicals. The quinones react by electron transfer with quenching rate constants k{sub q}(NQ) = 3 {times} 10{sup 9} and k{sub q}(AQS) = 4 {times} 10{sup 8} M{sup {minus}1} s{sup {minus}1}, giving anion radicals with primary yields of {phi}{sub R}(NQ) {approximately} 0.7 and {phi}{sub R}(AQS) {approximately} 0.3. Formic acid quenches {sup 3}AQS much more slowly. The less strongly oxidizing ketone triplets react by H-atom abstraction, k{sub q}(BC) = 1.3 {times} 10{sup 7} and k{sub q}(BS) = 5.3 {times} 10{sup 7} M{sup {minus}1} s{sup {minus}1}, giving protonated ketyl radicals with primary yields {phi}{sub R} {approximately} 0.7. Photoreduction of BC exhibits a deuterium isotope effect, k{sub H}/k{sub D} = 1.6, whereas AQS shows none. A new, short-lived transient, E, is observed in the {sup 3}AQS-formate reaction, which may be an exciplex or adduct. The redox potential, E{degree}{prime}(NQ/NQ{sup {sm bullet}{minus}}) = {minus}0.12 V, and rate constants for radical reactions of NQ and O{sub 2} were measured by pulse radiolysis. The results are discussed in terms of pertinent redox potentials, bond strengths, and the nature of the exciplex intermediates.

  8. Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), isolated from Plumbago zeylanica, inhibits ultraviolet radiation-induced development of squamous cell carcinomas

    PubMed Central

    Sand, Jordan M.; Hafeez, Bilal Bin; Jamal, Mohammad Sarwar; Witkowsky, Olya; Siebers, Emily M.; Fischer, Joseph; Verma, Ajit K.

    2012-01-01

    Plumbagin (PL) (5-hydroxy-2-methyl-1,4-napthoquinone), a medicinal plant-derived naphthoquinone, was isolated from the roots of the Plumbago zeylanica L. (also known as Chitrak). The roots of P. zeylanica L. have been used in Indian medicine for >2500 years as an anti-atherogenic, cardiotonic, hepatoprotective and neuroprotective agent. We present here that topical application of non-toxic doses (100–500 nmol) of PL to skin elicits dose-dependent inhibition of ultraviolet radiation (UVR)-induced development of squamous cell carcinomas (SCC). In this experiment, FVB/N mice were exposed to UVR (2 kJ/m2) three times weekly from a bank of six Kodacel-filtered FS40 sunlamps (∼60% UVB and 40% UVA). Carcinoma incidence in mice treated with vehicle, 100, 200 or 500 nmol PL, at 44 weeks post-UVR, were 86, 80 (P = 0.67), 53 (P = 0.12) and 7% (P = 0.0075), respectively. Both vehicle and PL-treated mice gained weight and did not exhibit any signs of toxicity during the entire period of the experiment. Molecular mechanisms associated with inhibition of UVR-induced development of SCC involved induction of apoptosis and inhibition of cell proliferation. Specific findings are that PL treatment (i) inhibited UVR-induced DNA binding of activating protein-1, nuclear factor-kappaB, Stat3 transcription factors and Stat3-regulated molecules (cdc25A and Survivin); (ii) inhibited protein levels of pERK1/2, PI3K85, pAKTSer473, Bcl2, BclxL, proliferating cell nuclear antigen and cell cycle inhibitory proteins p27 and p21 and (iii) increased UVR-induced Fas-associated death domain expression, poly (ADP-ribose) polymerase protein cleavage and Bax/Bcl2 ratio. Taken together, our findings suggest that PL may be a novel agent for the prevention of skin cancer. PMID:22072620

  9. Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

    PubMed Central

    de Castro, Solange L.; Batista, Denise G. J.; Batista, Marcos M.; Batista, Wanderson; Daliry, Anissa; de Souza, Elen M.; Menna-Barreto, Rubem F. S.; Oliveira, Gabriel M.; Salomão, Kelly; Silva, Cristiane F.; Silva, Patricia B.; Soeiro, Maria de Nazaré C.

    2011-01-01

    investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi. PMID:22091400

  10. Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones.

    PubMed

    de Castro, Solange L; Batista, Denise G J; Batista, Marcos M; Batista, Wanderson; Daliry, Anissa; de Souza, Elen M; Menna-Barreto, Rubem F S; Oliveira, Gabriel M; Salomão, Kelly; Silva, Cristiane F; Silva, Patricia B; Soeiro, Maria de Nazaré C

    2011-01-01

    investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi. PMID:22091400

  11. Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones.

    PubMed

    de Castro, Solange L; Batista, Denise G J; Batista, Marcos M; Batista, Wanderson; Daliry, Anissa; de Souza, Elen M; Menna-Barreto, Rubem F S; Oliveira, Gabriel M; Salomão, Kelly; Silva, Cristiane F; Silva, Patricia B; Soeiro, Maria de Nazaré C

    2011-01-01

    investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.

  12. Oxygen uptake upon photolysis of 1,4-benzoquinones and 1,4-naphthoquinones in air-saturated aqueous solution in the presence of formate, amines, ascorbic acid, and alcohols.

    PubMed

    Görner, Helmut

    2007-04-19

    The effects of oxygen in the photoreduction of 1,4-benzoquinone (BQ), 1,4-naphthoquinone (NQ), and a series of derivatives were studied in aqueous solution in the presence of acetonitrile and formate, aliphatic amines, e.g., EDTA or triethylamine, ascorbic acid, and alcohols, e.g., methanol or 2-propanol. The quinone triplet state is quenched, whereby the semiquinone and donor radicals are formed which react subsequently with oxygen. The overall reaction is oxidation of the donors and conversion of oxygen via the hydroperoxyl/superoxide radical into hydrogen peroxide. The quantum yield (Phi-O2) of this oxygen uptake changes in 2-propanol-water (1:10) from <0.01 for BQ to Phi-O2 = 0.5-0.8 for NQ. Generally Phi-O2 increases with increasing donor concentration. The specific properties of quinone structure, the radical equilibria and reactivity, and the concentration dependences are discussed. PMID:17388578

  13. Identification and characterization of a novel cross-link lesion in d(CpC) upon 365-nm irradiation in the presence of 2-methyl-1,4-naphthoquinone

    PubMed Central

    Liu, Zhenjiu; Gao, Yuan; Wang, Yinsheng

    2003-01-01

    We report the isolation and characterization for the first time of a cross-link lesion between two adjacent cytosines from the 2-methyl-1,4-naphthoquinone (menadione)-sensitized 365-nm irradiation of d(CpC). Electrospray ionization mass spectrometry (ESI-MS), tandem MS and 1H NMR results indicate that the cross-link occurs between the C5 carbon atom of one cytosine and the N4 nitrogen atom of the other cytosine. Furthermore, we synthesized d(CpC) with a 15N being incorporated on the amino group of either of the two cytosines. We then irradiated the two 15N-labeled dinucleoside monophosphates, isolated the cross-link products and characterized them by MS and multi-stage tandem MS. The latter results established unambiguously that the N4 nitrogen atom of the 3′-nucleobase is involved in the covalent bond formation between the two cytosines. This, in combination with two-dimensional nuclear Overhauser effect spectroscopy (NOESY) results, demonstrates that the cross-link arises from the formation of a covalent bond between the C5 carbon atom of the 5′ cytosine and the N4 nitrogen atom of the 3′ cytosine. We also show that the solution pH has a significant effect on the formation of the cross-link lesion, which supports that the deprotonation at the exocyclic amino group of cytosine cation radical is essential for the formation of the cross-link lesion. PMID:12954778

  14. Charge-transfer reaction of 2,3-dichloro-1,4-naphthoquinone with crizotinib: Spectrophotometric study, computational molecular modeling and use in development of microwell assay for crizotinib.

    PubMed

    Alzoman, Nourah Z; Alshehri, Jamilah M; Darwish, Ibrahim A; Khalil, Nasr Y; Abdel-Rahman, Hamdy M

    2015-01-01

    The reaction of 2,3-dichloro-1,4-naphthoquinone (DCNQ) with crizotinib (CZT; a novel drug used for treatment of non-small cell lung cancer) was investigated in different solvents of varying dielectric constants and polarity indexes. The reaction produced a red-colored product. Spectrophotometric investigations confirmed that the reaction proceeded through charge-transfer (CT) complex formation. The molar absorptivity of the complex was found to be linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9567 and 0.9069, respectively. The stoichiometric ratio of DCNQ:CZT was found to be 2:1 and the association constant of the complex was found to be 1.07 × 10(2) l/mol. The kinetics of the reaction was studied; the order of the reaction, rate and rate constant were determined. Computational molecular modeling for the complex between DCNQ and CZT was conducted, the sites of interaction on CZT molecule were determined, and the mechanism of the reaction was postulated. The reaction was employed as a basis in the development of a novel 96-microwell assay for CZT in a linear range of 4-500 μg/ml. The assay limits of detection and quantitation were 2.06 and 6.23 μg/ml, respectively. The assay was validated as per the guidelines of the International Conference on Harmonization (ICH) and successfully applied to the analysis of CZT in its bulk and capsules with good accuracy and precision. The assay has high throughput and consumes a minimum volume of organic solvents thus it reduces the exposures of the analysts to the toxic effects of organic solvents, and significantly reduces the analysis cost.

  15. Modulation of plasminogen activator inhibitor-1 (PAI-1) by the naphthoquinone shikonin.

    PubMed

    Han, Tingting; Zhang, Guangping; Yan, Dong; Yang, Hong; Ma, Tonghui; Ye, Zuguang

    2016-09-01

    Plasminogen activator inhibitor-1 (PAI-1) is a key negative regulator of the fibrinolytic system. Elevated levels of PAI-1 are associated with thrombosis and cardiovascular and metabolic diseases. Inhibition of PAI-1 activity represents a new strategy for antithrombotic and antifibrinolysis therapies. In this study, we systematically investigated the inhibitory effect of shikonin on PAI-1 activity. In the chromogenic substrate-based urokinase (uPA)/PAI-1 assay, we found that shikonin inhibited human PAI-1 activity with IC50 values of 30.68±2.32μM. This result was further confirmed by urokinase-type plasminogen activator (uPA)-mediated clot lysis assay. Mechanistic studies indicated that shikonin directly could bind to PAI-1 and prevent the binding of PAI-1 to uPA in a dose-dependent manner. Shikonin also blocked the formation of PAI-1/uPA complex, as shown by SDS/PAGE analysis. In the mouse arterial thrombosis model, intraperitoneal injection of shikonin at 1mgkg(-1) dose significantly prolonged tail bleeding time from 12.956±4.457min to 26.576±2.443min. It also reduced arterial thrombus weight from 0.01±0.001g to 0.006±0.001g (p<0.05). In a liver fibrosis treatment model, when shikonin was continuously injected intraperitoneally at a dose of 1mgkg(-1) over a two-week period, the hydroxyproline content in the mice plasma was significantly reduced and the degree of liver fibrosis was decreased significantly. Thus, shikonin may represent a novel small molecule inhibitor of PAI-1 that could have become a lead drug the treatment of thrombus and fibrosis. PMID:27476618

  16. Modulation of plasminogen activator inhibitor-1 (PAI-1) by the naphthoquinone shikonin.

    PubMed

    Han, Tingting; Zhang, Guangping; Yan, Dong; Yang, Hong; Ma, Tonghui; Ye, Zuguang

    2016-09-01

    Plasminogen activator inhibitor-1 (PAI-1) is a key negative regulator of the fibrinolytic system. Elevated levels of PAI-1 are associated with thrombosis and cardiovascular and metabolic diseases. Inhibition of PAI-1 activity represents a new strategy for antithrombotic and antifibrinolysis therapies. In this study, we systematically investigated the inhibitory effect of shikonin on PAI-1 activity. In the chromogenic substrate-based urokinase (uPA)/PAI-1 assay, we found that shikonin inhibited human PAI-1 activity with IC50 values of 30.68±2.32μM. This result was further confirmed by urokinase-type plasminogen activator (uPA)-mediated clot lysis assay. Mechanistic studies indicated that shikonin directly could bind to PAI-1 and prevent the binding of PAI-1 to uPA in a dose-dependent manner. Shikonin also blocked the formation of PAI-1/uPA complex, as shown by SDS/PAGE analysis. In the mouse arterial thrombosis model, intraperitoneal injection of shikonin at 1mgkg(-1) dose significantly prolonged tail bleeding time from 12.956±4.457min to 26.576±2.443min. It also reduced arterial thrombus weight from 0.01±0.001g to 0.006±0.001g (p<0.05). In a liver fibrosis treatment model, when shikonin was continuously injected intraperitoneally at a dose of 1mgkg(-1) over a two-week period, the hydroxyproline content in the mice plasma was significantly reduced and the degree of liver fibrosis was decreased significantly. Thus, shikonin may represent a novel small molecule inhibitor of PAI-1 that could have become a lead drug the treatment of thrombus and fibrosis.

  17. Synthesis and Biological Evaluation of Naphthoquinone Analogs as a Novel Class of Proteasome Inhibitors

    PubMed Central

    Lawrence, Harshani R.; Kazi, Aslamuzzaman; Luo, Yunting; Kendig, Robert; Ge, Yiyu; Jain, Sanjula; Daniel, Kenyon; Santiago, Daniel; Guida, Wayne C.; Sebti, Saïd M.

    2012-01-01

    Screening of the NCI Diversity Set-1 identified PI-083 (NSC-45382) a proteasome inhibitor selective for cancer over normal cells. Focused libraries of novel compounds based on PI-083 chloronaphthoquinone and sulfonamide moieties were synthesized to gain a better understanding of the structure activity relationship responsible for chymotrypsin-like proteasome inhibitory activity. This led to the demonstration that the chloronaphthoquinone and the sulfonamide moieties are critical for inhibitory activity. The pyridyl group in PI-083 can be replaced with other heterocyclic groups without significant loss of activity. Molecular modeling studies were also performed to explore the detailed interactions of PI-083 and its derivatives with the β5 and β6 subunits of the 20S proteasome. The refined model showed an H-bond interaction between the Asp-114 and the sulfonamide moiety of the PI-083 in the β6 subunit. PMID:20621484

  18. Generic inhibition of amyloidogenic proteins by two naphthoquinone-tryptophan hybrid molecules.

    PubMed

    Scherzer-Attali, Roni; Shaltiel-Karyo, Ronit; Adalist, Yonatan H; Segal, Daniel; Gazit, Ehud

    2012-08-01

    Amyloid formation is associated with several human diseases including Alzheimer's disease (AD), Parkinson's disease, Type 2 Diabetes, and so forth, no disease modifying therapeutics are available for them. Because of the structural similarities between the amyloid species characterizing these diseases, (despite the lack of amino acid homology) it is believed that there might be a common mechanism of toxicity for these conditions. Thus, inhibition of amyloid formation could be a promising disease-modifying therapeutic strategy for them. Aromatic residues have been identified as crucial in formation and stabilization of amyloid structures. This finding was corroborated by high-resolution structural studies, theoretical analysis, and molecular dynamics simulations. Amongst the aromatic entities, tryptophan was found to possess the most amyloidogenic potential. We therefore postulate that targeting aromatic recognition interfaces by tryptophan could be a useful approach for inhibiting the formation of amyloids. Quinones are known as inhibitors of cellular metabolic pathways, to have anti- cancer, anti-viral and anti-bacterial properties and were shown to inhibit aggregation of several amyloidogenic proteins in vitro. We have previously described two quinone-tryptophan hybrids which are capable of inhibiting amyloid-beta, the protein associated with AD pathology, both in vitro and in vivo. Here we tested their generic properties and their ability to inhibit other amyloidogenic proteins including α-synuclein, islet amyloid polypeptide, lysozyme, calcitonin, and insulin. Both compounds showed efficient inhibition of all five proteins examined both by ThT fluorescence analysis and by electron microscope imaging. If verified in vivo, these small molecules could serve as leads for developing generic anti-amyloid drugs.

  19. Generation of naphthoquinone radical anions by electrospray ionization: solution, gas-phase, and computational chemistry studies.

    PubMed

    Vessecchi, Ricardo; Naal, Zeki; Lopes, José N C; Galembeck, Sérgio E; Lopes, Norberto P

    2011-06-01

    Radical anions are present in several chemical processes, and understanding the reactivity of these species may be described by their thermodynamic properties. Over the last years, the formation of radical ions in the gas phase has been an important issue concerning electrospray ionization mass spectrometry studies. In this work, we report on the generation of radical anions of quinonoid compounds (Q) by electrospray ionization mass spectrometry. The balance between radical anion formation and the deprotonated molecule is also analyzed by influence of the experimental parameters (gas-phase acidity, electron affinity, and reduction potential) and solvent system employed. The gas-phase parameters for formation of radical species and deprotonated species were achieved on the basis of computational thermochemistry. The solution effects on the formation of radical anion (Q(•-)) and dianion (Q(2-)) were evaluated on the basis of cyclic voltammetry analysis and the reduction potentials compared with calculated electron affinities. The occurrence of unexpected ions [Q+15](-) was described as being a reaction between the solvent system and the radical anion, Q(•-). The gas-phase chemistry of the electrosprayed radical anions was obtained by collisional-induced dissociation and compared to the relative energy calculations. These results are important for understanding the formation and reactivity of radical anions and to establish their correlation with the reducing properties by electrospray ionization analyses. PMID:21561138

  20. Synthesis and evaluation of antitumor activity of 2- and 6-[(1,3-benzothiazol-2-yl)aminomethyl]-5,8-dimethoxy-1,4-naphthoquinone derivatives.

    PubMed

    Chung, Yongseog; Shin, Young-Kook; Zhan, Chang-Guo; Lee, Sungduck; Cho, Hoon

    2004-09-01

    2- or 6-substituted BZT-N derivatives were synthesized, and their cytotoxic activity against cancer L1210 and SNU-1 cells was examined. The antitumor action was also assessed in mice bearing S-180 cells in peritoneal cavity. In a comparison, it was found that 6-substituted BZT-N derivatives exhibited higher potencies in both bioactivities than 2-substituted BZT-N derivatives against L1210 cells in in vitro and S-180 in vitro tests exception of compound 36. Interestingly, it was observed that 2-substituted compound 36, which has methyl group at R1 position, exhibited a better antitumor activity than 6-substituted compounds against L1210 and SNU-1 in vitro. The ED50 value of 2-substituted compound 36 against L1210 was found to be comparable to the ED50 value of adriamycin and was even better against the solid cancer cell line SNU-1. It was also observed that 2-substituted compound 36 showed better antitumor activity in mice bearing S-180 cells in the peritoneal cavity. The T/C (%) value of 2-substituted compound 36 was similar to that of adriamycin. Quantitative structure-activity relationship (QSAR) tests reveal that the experimental ED50 values against SNU-1 closely correlate with both the calculated HOMO energies (E(HOMO)) and the measured 1H-NMR chemical shift of 3-H (deltaH). The results suggests that a compound having higher E(HOMO) and deltaH values usually should have a lower ED50 (SNU-1) value.

  1. Reactive Sulfur Species-Mediated Activation of the Keap1-Nrf2 Pathway by 1,2-Naphthoquinone through Sulfenic Acids Formation under Oxidative Stress.

    PubMed

    Shinkai, Yasuhiro; Abiko, Yumi; Ida, Tomoaki; Miura, Takashi; Kakehashi, Hidenao; Ishii, Isao; Nishida, Motohiro; Sawa, Tomohiro; Akaike, Takaaki; Kumagai, Yoshito

    2015-05-18

    Sulfhydration by a hydrogen sulfide anion and electrophile thiolation by reactive sulfur species (RSS) such as persulfides/polysulfides (e.g., R-S-SH/R-S-Sn-H(R)) are unique reactions in electrophilic signaling. Using 1,2-dihydroxynaphthalene-4-thioacetate (1,2-NQH2-SAc) as a precursor to 1,2-dihydroxynaphthalene-4-thiol (1,2-NQH2-SH) and a generator of reactive oxygen species (ROS), we demonstrate that protein thiols can be modified by a reactive sulfenic acid to form disulfide adducts that undergo rapid cleavage in the presence of glutathione (GSH). As expected, 1,2-NQH2-SAc is rapidly hydrolyzed and partially oxidized to yield 1,2-NQ-SH, resulting in a redox cycling reaction that produces ROS through a chemical disproportionation reaction. The sulfenic acid forms of 1,2-NQ-SH and 1,2-NQH2-SH were detected by derivatization experiments with dimedone. 1,2-NQH2-SOH modified Keap1 at Cys171 to produce a Keap1-S-S-1,2-NQH2 adduct. Subsequent exposure of A431 cells to 1,2-NQ or 1,2-NQH2-SAc caused an extensive chemical modification of cellular proteins in both cases. Protein adduction by 1,2-NQ through a thio ether (C-S-C) bond slowly declined through a GSH-dependent S-transarylation reaction, whereas that originating from 1,2-NQH2-SAc through a disulfide (C-S-S-C) bond was rapidly restored to the free protein thiol in the cells. Under these conditions, 1,2-NQH2-SAc activated Nrf2 and upregulated its target genes, which were enhanced by pretreatment with buthionine sulfoximine (BSO), to deplete cellular GSH. Pretreatment of catalase conjugated with poly(ethylene glycol) suppressed Nrf2 activation by 1,2-NQH2-SAc. These results suggest that RSS-mediated reversible electrophilic signaling takes place through sulfenic acids formation under oxidative stress. PMID:25807370

  2. Ramentaceone, a Naphthoquinone Derived from Drosera sp., Induces Apoptosis by Suppressing PI3K/Akt Signaling in Breast Cancer Cells

    PubMed Central

    Kawiak, Anna; Lojkowska, Ewa

    2016-01-01

    The phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in processes critical for breast cancer progression and its upregulation confers increased resistance of cancer cells to chemotherapy and radiation. The present study aimed at determining the activity of ramentaceone, a constituent of species in the plant genera Drosera, toward breast cancer cells and defining the involvement of PI3K/Akt inhibition in ramentaceone-mediated cell death induction. The results showed that ramentaceone exhibited high antiproliferative activity toward breast cancer cells, in particular HER2-overexpressing breast cancer cells. The mode of cell death induced by ramentaceone was through apoptosis as determined by cytometric analysis of caspase activity and Annexin V staining. Apoptosis induction was found to be mediated by inhibition of PI3K/Akt signaling and through targeting its downstream anti-apoptotic effectors. Ramentaceone inhibited PI3-kinase activity, reduced the expression of the PI3K protein and inhibited the phosphorylation of the Akt protein in breast cancer cells. The expression of the anti-apoptotic Bcl-2 protein was decreased and the levels of the pro-apoptotic proteins, Bax and Bak, were elevated. Moreover, inhibition of PI3K and silencing of Akt expression increased the sensitivity of cells to ramentaceone-induced apoptosis. In conclusion, our results indicate that ramentaceone induces apoptosis in breast cancer cells through PI3K/Akt signaling inhibition. These findings suggest further investigation of ramentaceone as a potential therapeutic agent in breast cancer therapy, in particular HER2-positive breast cancer. PMID:26840401

  3. DIFFERENTIATING MECHANISMS OF REACTIVE CHEMICAL TOXICITY IN ISOLATED TROUT HEPATOCYTES

    EPA Science Inventory

    The toxicity of four quinones, 2,3-dimethoxy-1,4-naphthoquinone (DMONQ), 2-methyl 1,4-naphthoquinone (MNQ ),1,4-naphthoquinone (NQ), and 1,4-benzoquinone (BQ), which redox cycle or arlyate in mammalian cells, was determined in isolated trout (Oncorhynchus mykiss) hepatocytes. Mor...

  4. Evidence of Polymorphism on the Antitrypanosomal Naphthoquinone (4E)-2-(1H-Pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one

    PubMed Central

    Sperandeo, Norma R.; Faudone, Sonia N.

    2013-01-01

    The aim of this study was to characterize the solid state properties of (4E)-2-(1H-pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one (BiPNQ), a compound with a significant inhibitory activity against Trypanosoma cruzi, the etiological agent of Chagas disease (American trypanosomiasis). Methods used included Differential Scanning Calorimetry (DSC), Thermogravimetry (TG), Fourier Transform Infrared Spectroscopy (FTIR), Powder X-Ray Diffraction (PXRD), Hot Stage, and Confocal Microscopy. Two BiPNQ samples were obtained by crystallization from absolute methanol and 2-propanol-water that exhibited different thermal behaviours, PXRD patterns, and FTIR spectra, indicating the existence of an anhydrous form (BiPNQ-I) and a solvate (BIPNQ-s), which on heating desolvated leading to the anhydrous modification BiPNQ-I. It was determined that FTIR, DSC, and PXRD are useful techniques for the characterization and identification of the crystalline modifications of BiPNQ. PMID:24106678

  5. Complexes of Lapachol and Lawsone with Lanthanides.

    PubMed

    Genovese, Salvatore; Taddeo, Vito Alessandro; Epifano, Francesco; Fiorito, Serena

    2015-11-01

    Naturally occurring 2-hydroxy-1,4-naphthoquinones are well known to form readily stable complexes with transition metals. In this short communication we describe for the first time the synthesis and preliminary data about structural characterization of complexes between two naturally widespread 2-hydroxy-1,4-naphthoquinones, namely lapachol (1) and lawsone (2), with selected lanthanides like lanthanum, gadolinium, and ytterbium. When tested as cytotoxic compounds, such complexes exhibited an activity that was either higher or equal to that of the parent naphthoquinone. PMID:26749803

  6. The Chemistry of Plant and Animal Dyes.

    ERIC Educational Resources Information Center

    Sequin-Frey, Margareta

    1981-01-01

    Provides a brief history of natural dyes. Chemical formulas are provided for flavonoids, luteolin, genistein, brazilin, tannins, terpenes, naphthoquinone, anthraquinone, and dyes with an alkaloid structure. Also discusses chemical background of different dye processes. (CS)

  7. Time-resolved visible and infrared absorption spectroscopy data obtained using photosystem I particles with non-native quinones incorporated into the A1 binding site.

    PubMed

    Makita, Hiroki; Hastings, Gary

    2016-06-01

    Time-resolved visible and infrared absorption difference spectroscopy data at both 298 and 77 K were obtained using cyanobacterial menB (-) mutant photosystem I particles with several non-native quinones incorporated into the A1 binding site. Data was obtained for photosystem I particles with phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone), 2-bromo-1,4-naphthoquinone, 2-chloro-1,4-naphthoquinone, 2-methyl-1,4-naphthoquinone, 2,3-dibromo-1,4-naphthoquinone, 2,3-dichloro-1,4-naphthoquinone, and 9,10-anthraquinone incorporated. Transient absorption data were obtained at 487 and 703 nm in the visible spectral range, and 1950-1100 cm(-1) in the infrared region. Time constants obtained from fitting the time-resolved infrared and visible data are in good agreement. The measured time constants are crucial for the development of appropriate kinetic models that can describe electron transfer processes in photosystem I, "Modeling Electron Transfer in Photosystem I" Makita and Hastings (2016) [1].

  8. In vitro Activation of heme oxygenase-2 by menadione and its analogs

    PubMed Central

    2014-01-01

    Background Previously, we reported that menadione activated rat, native heme oxygenase-2 (HO-2) and human recombinant heme oxygenase-2 selectively; it did not activate spleen, microsomal heme oxygenase-1. The purpose of this study was to explore some structure–activity relationships of this activation and the idea that redox properties may be an important aspect of menadione efficacy. Methods Heme oxygenase activity was determined in vitro using rat spleen and brain microsomes as the sources of heme oxygenase-1 and −2, respectively, as well as recombinant, human heme oxygenase-2. Results Menadione analogs with bulky aliphatic groups at position-3, namely vitamins K1 and K2, were not able to activate HO-2. In contrast, several compounds with similar bulky but less lipophilic moieties at position-2 (and −3) were able to activate HO-2 many fold; these compounds included polar, rigid, furan-containing naphthoquinones, furan-benzoxazine naphthoquinones, 2-(aminophenylphenyl)-3-piperidin-1-yl naphthoquinones. To explore the idea that redox properties might be involved in menadione efficacy, we tested analogs such as 1,4-dimethoxy-2-methylnaphthalene, pentafluoromenadione, monohalogenated naphthoquinones, α-tetralone and 1,4-naphthoquinone. All of these compounds were inactive except for 1,4-naphthoquinone. Menadione activated full-length recombinant human heme oxygenase-2 (FL-hHO-2) as effectively as rat brain enzyme, but it did not activate rat spleen heme oxygenase. Conclusions These observations are consistent with the idea that naphthoquinones such as menadione bind to a receptor in HO-2 and activate the enzyme through a mechanism that may involve redox properties. PMID:24533775

  9. Biologically Active Metabolites Produced by the Basidiomycete Quambalaria cyanescens

    PubMed Central

    Stodůlková, Eva; Císařová, Ivana; Kolařík, Miroslav; Chudíčková, Milada; Novák, Petr; Man, Petr; Kuzma, Marek; Pavlů, Barbora; Černý, Jan; Flieger, Miroslav

    2015-01-01

    Four strains of the fungus Quambalaria cyanescens (Basidiomycota: Microstromatales), were used for the determination of secondary metabolites production and their antimicrobial and biological activities. A new naphthoquinone named quambalarine A, (S)-(+)-3-(5-ethyl-tetrahydrofuran-2-yliden)-5,7,8-trihydroxy-2-oxo-1,4-naphthoquinone (1), together with two known naphthoquinones, 3-hexanoyl-2,5,7,8-tetrahydroxy-1,4-naphthoquinone (named here as quambalarine B, 2) and mompain, 2,5,7,8-tetrahydroxy-1,4-naphthoquinone (3) were isolated. Their structures were determined by single-crystal X-ray diffraction crystallography, NMR and MS spectrometry. Quambalarine A (1) had a broad antifungal and antibacterial activity and is able inhibit growth of human pathogenic fungus Aspergillus fumigatus and fungi co-occurring with Q. cyanescens in bark beetle galleries including insect pathogenic species Beauveria bassiana. Quambalarine B (2) was active against several fungi and mompain mainly against bacteria. The biological activity against human-derived cell lines was selective towards mitochondria (2 and 3); after long-term incubation with 2, mitochondria were undetectable using a mitochondrial probe. A similar effect on mitochondria was observed also for environmental competitors of Q. cyanescens from the genus Geosmithia. PMID:25723150

  10. Cataractogenicity and bioactivation of naphthalene derivatives in lens culture and in vivo

    SciTech Connect

    Lubek, B.M.; Kubow, S.; Basu, P.K.; Wells, P.G. )

    1989-01-01

    The cataractogenicity of naphthalene derivatives was investigated in a lens culture system that included the lens with an intact capsule and epithelium. The in vivo cataractogenicity of naphthalene, 1000 or 2000 mg/kg ip, also was evaluated in New Zealand white and Chinchilla pigmented rabbits. A dose-related brunescence was observed in lenses incubated with 1,4-naphthoquinone in concentrations from 31.6 to 316 microM. With 316 microM naphthoquinone, lenses were totally opaque within 24 hr. No lenticular opacities were observed with 1-naphthol or 2-naphthol in incubations lasting up to 96 hr. The bioactivation of naphthalene derivatives to reactive free radical intermediates by lenses in organ culture was investigated by electron spin resonance spectrometry (ESR) using the spin trap alpha-phenyl-N-t-butylnitrone (PBN). Lenses were incubated with 316 microM naphthoquinone and 100 mM PBN for 0.25, 4 or 7 hr. A spin trapped radical product with unresolved peaks was observed with 0.25 and 7 hr incubation. No radicals were detected in the 4 hr incubation, nor in control cultures lacking either the lens, naphthoquinone or PBN. In the in vivo studies, naphthalene was cataractogenic in both albino and pigmented rabbits. The in vitro results indicate that naphthoquinone can be bioactivated by rabbit lens to a reactive free radical intermediate, which may contribute to cataractogenicity.

  11. Chemical composition fluctuations in roots of Plumbago scandens L. in relation to floral development.

    PubMed

    Paiva, Selma R; Lima, Lucilene A; Figueiredo, Maria Raquel; Kaplan, Maria Auxiliadora C

    2011-12-01

    Plumbago scandens L. is a Brazilian tropical/subtropical species that occurs along the coast. Chemically it is mainly represented by naphthoquinones, flavonoids, terpenoids and steroids. The aim of the present work is to study quantitative changes in the root metabolic production of Plumbago scandens during different physiologic developmental stages relative to floration. The results indicated the presence of four substances in the extracts: plumbagin, epi-isoshinanolone, palmitic acid and sitosterol, independent on developmental stage. The naphthoquinone plumbagin has always showed to be the major component of all extracts. Naphthoquinones exhibited their highest content during floration, while the content of the two others components decreased during this stage, revealing an inverse profile. The chemical composition changed depending on the plant requirements. PMID:22146952

  12. Redox activity of naphthalene secondary organic aerosol

    NASA Astrophysics Data System (ADS)

    McWhinney, R. D.; Zhou, S.; Abbatt, J. P. D.

    2013-04-01

    Chamber secondary organic aerosol (SOA) from low-NOx photooxidation of naphthalene by hydroxyl radical was examined with respect to its redox cycling behaviour using the dithiothreitol (DTT) assay. Naphthalene SOA was highly redox active, consuming DTT at an average rate of 118 ± 14 pmol per minute per μg of SOA material. Measured particle-phase masses of the major previously identified redox active products, 1,2- and 1,4-naphthoquinone, accounted for only 21 ± 3% of the observed redox cycling activity. The redox-active 5-hydroxy-1,4-naphthoquinone was identified as a new minor product of naphthalene oxidation, and including this species in redox activity predictions increased the predicted DTT reactivity to 30 ± 5% of observations. Similar attempts to predict redox behaviour of oxidised two-stroke engine exhaust particles by measuring 1,2-naphthoquinone, 1,4-naphthoquinone and 9,10-phenanthrenequinone predicted DTT decay rates only 4.9 ± 2.5% of those observed. Together, these results suggest that there are substantial unidentified redox-active SOA constituents beyond the small quinones that may be important toxic components of these particles. A gas-to-SOA particle partitioning coefficient was calculated to be (7.0 ± 2.5) × 10-4 m3 μg-1 for 1,4-naphthoquinone at 25 °C. This value suggests that under typical warm conditions, 1,4-naphthoquinone is unlikely to contribute strongly to redox behaviour of ambient particles, although further work is needed to determine the potential impact under conditions such as low temperatures where partitioning to the particle is more favourable. As well, higher order oxidation products that likely account for a substantial fraction of the redox cycling capability of the naphthalene SOA are likely to partition much more strongly to the particle phase.

  13. Quinone derivatives from the genus Rubia and their bioactivities.

    PubMed

    Xu, Kuo; Wang, Penglong; Wang, Lin; Liu, Congmin; Xu, Shixun; Cheng, Yatao; Wang, Yanhui; Li, Qiang; Lei, Haimin

    2014-03-01

    The extracts and phytochemicals of the genus Rubia have drawn much attention due to their potent effects; among them, naphthoquinone and cyclopeptide derivatives, with significant biological activities, have great potential to be developed to new drugs. This review updates and compiles a total of 142 quinone derivatives including anthraquinone and naphthoquinone derivatives, occuring in twelve Rubia species. These compounds were listed together with their sources, melting points, bioactivities, as well as 112 corresponding references. Furthermore, the structureactivity relationships of these quinone derivatives were discussed.

  14. Microbial transformations of natural antitumor agents: oxidation of lapachol by Penicillium notatum.

    PubMed Central

    Otten, S; Rosazza, J P

    1978-01-01

    The naphthoquinone lapachol (1) is readily metabolized by several fungi and streptomycetes. Preparative-scale fermentations with Penicillium notatum (UI 1602) provided a major polar metabolite (4), which was isolated and identified as an intermediate of the Hooker oxidation. The metabolite was synthesized by reacting lapachol with hydrogen peroxide under alkaline conditions. PMID:637549

  15. Vitamin K

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vitamin K was identified in the early 1930’s when it was shown to be essential for normal blood coagulation. Phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone) found in green plants is the major source of the vitamin. Large amounts of menaquinones with lengthy side chains are also synthesized in...

  16. Comparative study of three Plumbago L. species (Plumbaginaceae) by microscopy, UPLC–UV and HPTLC analyses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This paper presents a comparative study of anatomy of leaves, stems and roots of three species of Plumbago, namely P. auriculata Lam., P. indica L. and P. zeylanica L. by light microscopy. The paper also provides qualitative and quantitative analysis of the naphthoquinone, plumbagin, a major constit...

  17. Quantum-chemical calculations and electron diffraction study of the equilibrium molecular structure of vitamin K3

    NASA Astrophysics Data System (ADS)

    Khaikin, L. S.; Tikhonov, D. S.; Grikina, O. E.; Rykov, A. N.; Stepanov, N. F.

    2014-05-01

    The equilibrium molecular structure of 2-methyl-1,4-naphthoquinone (vitamin K3) having C s symmetry is experimentally characterized for the first time by means of gas-phase electron diffraction using quantum-chemical calculations and data on the vibrational spectra of related compounds.

  18. Protein Sulfenylation: A Novel Readout of Environmental Oxidant Stress

    EPA Science Inventory

    Oxidative stress is a commonly cited mechanism of toxicity of environmental agents. Ubiquitous environmental chemicals such as the diesel exhaust component 1,2-naphthoquinone (1,2-NQ)induce oxidative stress by redox cycling, which generates hydrogen peroxide (H202). Cysteinylthio...

  19. Stabilization and detection of hydrophylloquinone as di-O-methyl derivative.

    PubMed

    Sussmann, Rodrigo A C; de Moraes, Marcilio M; Cebrián-Torrejón, Gerardo; Porta, Exequiel O; Doménech-Carbó, Antonio; Yamaguchi, Lydia F; Katzin, Alejandro M; Kato, Massuo J

    2016-10-15

    Phylloquinone is a redox active naphthoquinone involved in electron transport in plants. The function of this reduced form remains unclear due to its instability, which has precluded detection. Herein, a simple method that permits the stabilization of the reduced form of phylloquinone by di-O-methylation and HPLC detection is described.

  20. Hydrogen Peroxide Formation in a Surrogate Lung Fluid by Transition Metals and Quinones Present in Particulate Matter

    PubMed Central

    2015-01-01

    Inhaled ambient particulate matter (PM) causes adverse health effects, possibly by generating reactive oxygen species (ROS), including hydrogen peroxide (HOOH), in the lung lining fluid. There are conflicting reports in the literature as to which chemical components of PM can chemically generate HOOH in lung fluid mimics. It is also unclear which redox-active species are most important for HOOH formation at concentrations relevant to ambient PM. To address this, we use a cell-free, surrogate lung fluid (SLF) to quantify the initial rate of HOOH formation from 10 transition metals and 4 quinones commonly identified in PM. Copper, 1,2-naphthoquinone, 1,4-naphthoquinone, and phenanthrenequinone all form HOOH in a SLF, but only copper and 1,2-naphthoquinone are likely important at ambient concentrations. Iron suppresses HOOH formation in laboratory solutions, but has a smaller effect in ambient PM extracts, possibly because organic ligands in the particles reduce the reactivity of iron. Overall, copper produces the majority of HOOH chemically generated from typical ambient PM while 1,2-naphthoquinone generally makes a small contribution. However, measured rates of HOOH formation in ambient particle extracts are lower than rates calculated from soluble copper by an average (±1σ) of 44 ± 22%; this underestimate is likely due to either HOOH destruction by Fe or a reduction in Cu reactivity due to organic ligands from the PM. PMID:24857372

  1. Hydrogen peroxide formation in a surrogate lung fluid by transition metals and quinones present in particulate matter.

    PubMed

    Charrier, Jessica G; McFall, Alexander S; Richards-Henderson, Nicole K; Anastasio, Cort

    2014-06-17

    Inhaled ambient particulate matter (PM) causes adverse health effects, possibly by generating reactive oxygen species (ROS), including hydrogen peroxide (HOOH), in the lung lining fluid. There are conflicting reports in the literature as to which chemical components of PM can chemically generate HOOH in lung fluid mimics. It is also unclear which redox-active species are most important for HOOH formation at concentrations relevant to ambient PM. To address this, we use a cell-free, surrogate lung fluid (SLF) to quantify the initial rate of HOOH formation from 10 transition metals and 4 quinones commonly identified in PM. Copper, 1,2-naphthoquinone, 1,4-naphthoquinone, and phenanthrenequinone all form HOOH in a SLF, but only copper and 1,2-naphthoquinone are likely important at ambient concentrations. Iron suppresses HOOH formation in laboratory solutions, but has a smaller effect in ambient PM extracts, possibly because organic ligands in the particles reduce the reactivity of iron. Overall, copper produces the majority of HOOH chemically generated from typical ambient PM while 1,2-naphthoquinone generally makes a small contribution. However, measured rates of HOOH formation in ambient particle extracts are lower than rates calculated from soluble copper by an average (±1σ) of 44 ± 22%; this underestimate is likely due to either HOOH destruction by Fe or a reduction in Cu reactivity due to organic ligands from the PM. PMID:24857372

  2. Phylloquinone (vitamin K1): occurrence, biosynthesis and functions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phylloquinone is a prenylated naphthoquinone that is synthesized exclusively by plants, green algae, and some species of cyanobacteria, where it serves as a vital electron carrier in photosystem I and as an electron acceptor for the formation of protein disulfide bonds. In humans and other vertebrat...

  3. Design and synthesis of propellane derivatives and oxa-bowls via ring-rearrangement metathesis as a key step

    PubMed Central

    Gunta, Rama

    2015-01-01

    Summary Various intricate propellane derivatives and oxa-bowls have been synthesized via a ring-rearrangement metathesis (RRM) as a key step starting from readily accessible starting materials such as p-benzoquinone, 1,4-naphthoquinone and 1,4-anthraquinone. PMID:26664592

  4. Mechanisms Of The Dissolution Inhibition Effect And Their Application To Designing Novel Deep-UV Resists

    NASA Astrophysics Data System (ADS)

    Murata, Makoto; Koshiba, Mitsunobu; Harita, Yoshiyuki

    1989-08-01

    The dissolution inhibition effect and alkaline solubility were investigated for naphthoquinone diazides like 1,2-naphthoquinone diazide (NQD), its 5-sulfonylchloride (NQD-C) and 5-sulfonyloxybenzene (DAM), and for other compounds like sulfonylchlorides, sulfonyl esters, sulfones and a ketone which do not contain a naphthoquinone diazide moiety. As a result, it has turned out that the dissolution inhibition effect does not depend on the specific structure; namely, the naphthoquinone diazide moiety itself, but largely on the alkaline solubility of the compounds added to a novolak resin. An XPS study for the films consisting of a novolak resin and a dissolution inhibitor indicates a formation of an inhibitor-rich protective thin layer on the film surface after immersion of the film in an alkaline developer. In this paper is proposed a new third dissolution inhibition mechanism in addition to the previously reported chemical crosslinking and dipolar interaction; i.e., the alkaline insoluble protective layer inhibits the dissolution of novolak resin at the interface between the film and the developer. A new three-component type deep-UV resist has been also developed as an application of the new mechanism. The resist consists of a novolak resin, 5-diazo Meldrum's acid and a new dissolution inhibitors like phenyltosylate and p-phenylene ditosylate, which successfully improve the residual resist thickness.

  5. [Anaerobic humus respiration by Shewanella cinica D14T].

    PubMed

    Xu, Zhi-cheng; Hong, Yi-guo; Luo, Wei; Chen, Xing-juan; Sun, Guo-ping; Xu, Mei-ying; Guo, Jun; Cen, Ying-hua

    2006-12-01

    Experimental results suggested Shewanella cinica D14T is capable of humus respiration utilizing various organic acids and some important environmental pollutants (e.g., toluene. etc) as electron donors and AQS or AQDS as a sole terminal electron acceptor under anaerobic condition. The dissimilatory reduction of 1mmol/L AQDS can couple to the production of enough ATP to support cell growth about 60 generations; The oxidization of electron donors was coupled to the reduction of humus, as reduced humus increased corresponding with increasing of electron donor; The typical inhibitors such as Cu2+ which inhibited Fe-S center, Stigmatellin which was methyl-naphthoquinone model, Dicumarol which inhibited oxidized methyl-naphthoquinone transform to reduced one, Metyrapone which was specific inhibitor for P450 enzyme blocked the humus respiration seriously. These were powerful evidences for humus-respiration by D14.

  6. Antitumoral and antileishmanial dioncoquinones and ancistroquinones from cell cultures of Triphyophyllum peltatum (Dioncophyllaceae) and Ancistrocladus abbreviatus (Ancistrocladaceae).

    PubMed

    Bringmann, Gerhard; Rüdenauer, Stefan; Irmer, Andreas; Bruhn, Torsten; Brun, Reto; Heimberger, Tanja; Stühmer, Thorsten; Bargou, Ralf; Chatterjee, Manik

    2008-10-01

    From the methanolic extracts of solid callus cultures from two species of the closely related palaeotropical plant families Dioncophyllaceae and Ancistrocladaceae seven new natural naphthoquinones were isolated, dioncoquinones A (4) and B (5) from Triphyophyllum peltatum, and ancistroquinones B (6), C (7), D (9), E (10), and F (12) from Ancistrocladus abbreviatus. Their structures were elucidated by spectroscopic, chemical, and computational methods. Furthermore, the already known naphthoquinones plumbagin (2), droserone (3), malvone A (8), and nepenthone A (11) were found in the extract of A. abbreviatus. Dioncoquinones A (4) and B (5) showed good - and specific - activity against Leishmania major, while they were not active against other protozoic parasites. Moreover, treatment with 4 and 5 strongly induced apoptosis in human tumor cells derived from two different B cell malignancies, B cell lymphoma and multiple myeloma, without any significant toxicity towards normal peripheral mononuclear blood cells. PMID:18723197

  7. Anti-diabetic activity of active fractions of Stereospermum tetragonum DC and isolation of active principles

    PubMed Central

    Bino Kingsley, Renjit; Mishra, Manisha; Brindha, Pemaiah; Subramoniam, Appian

    2013-01-01

    Objectives To identify the active principles, determine the anti-diabetes activity of fraction of Stereospermum tetragonum root. Materials and Methods The efficacy was evaluated in streptozotocin induced type 2 diabetic rats and the anti-hyperglycemic activity was studied by glucose tolerance test. The major active compounds were isolated by solvent fractionation and chromatographic techniques and characterized with spectral data. Results The active fraction of S. tetragonum showed presence of anti-diabetes mellitus activity in type-2 diabetic rats. It did not significantly influence insulin release from cultured islets. Two active principles (active at 2 mg/kg dose) were isolated and characterized with spectral data. One of them was identified as an iridoid type glycoside and the other one was a lapachol like compound (derivative of naphthoquinone). Conclusions Two active principles from the anti-diabetes fraction of S. tetragonum root were isolated and identified as an iridoid glycoside and a naphthoquinone derivative. PMID:24023445

  8. Copper(i)-Y zeolite catalyzed N-sulfonylketenimine mediated annulation of hydroxynaphthoquinones: syntheses of naphtho[2,1-b]furan-2,5-diones and benzo[de]chromene-2,6-diones.

    PubMed

    Ramanathan, Devenderan; Namitharan, Kayambu; Pitchumani, Kasi

    2016-06-28

    An efficient one pot synthesis for the construction of novel naphtho[2,1-b]furan-2,5-diones and benzo[de]chromene-2,6-diones using copper(i)-Y zeolite catalyzed reaction of N-sulfonylketenimine with 2-hydroxy-1,4-naphthoquinone and 5-hydroxy-1,4-naphthoquinone followed by the elimination of p-toluenesulfonamide is reported. The intermediate N-sulfonylketenimine, generated by (3+2) cycloaddition/ring-opening reaction/retro-Wolff rearrangement, cascade, and annulation, promotes the reaction involving the inter- and intramolecular nucleophilic addition/dehydration followed by hydrolysis and elimination of p-toluenesulfonamide to afford the target products in good yield. PMID:27305854

  9. Enantioselective synthesis of 4H-pyranonaphthoquinones via sequential squaramide and silver catalysis.

    PubMed

    Kaya, Uğur; Chauhan, Pankaj; Hack, Daniel; Deckers, Kristina; Puttreddy, Rakesh; Rissanen, Kari; Enders, Dieter

    2016-01-28

    An enantioselective one-pot Michael addition/hydroalkoxylation reaction between 2-hydroxy-1,4-naphthoquinones and alkyne-tethered nitroalkenes catalyzed by a cinchona-derived squaramide and a silver(I) salt has been developed. The sequential protocol provides a direct access to 4H-pyranonaphthoquinones in moderate to very good yields and good to excellent enantioselectivities at a very low catalyst loading (0.5 mol%) of the squaramide.

  10. Effects of the chitin synthetase inhibitor plumbagin and its 2-demethyl derivative juglone on insect ecdysone 20-monooxygenase activity.

    PubMed

    Mitchell, M J; Smith, S L

    1988-12-01

    The chitin synthetase inhibitor plumbagin and its 2-demethyl derivative juglone were found to inhibit in a dose-response fashion the cytochrome P-450 dependent ecdysone 20-monooxygenase activity associated with adult female Aedes aegypti, wandering stage larvae of Drosophila melanogaster, and fat body and midgut from last instar larvae of Manduca sexta. The concentration of these naphthoquinones required to elicit a 50% inhibition of the steroid hydroxylase activity in all the insects was approximately 1 x 10(-4) M.

  11. Enantioselective synthesis of 4H-pyranonaphthoquinones via sequential squaramide and silver catalysis.

    PubMed

    Kaya, Uğur; Chauhan, Pankaj; Hack, Daniel; Deckers, Kristina; Puttreddy, Rakesh; Rissanen, Kari; Enders, Dieter

    2016-01-28

    An enantioselective one-pot Michael addition/hydroalkoxylation reaction between 2-hydroxy-1,4-naphthoquinones and alkyne-tethered nitroalkenes catalyzed by a cinchona-derived squaramide and a silver(I) salt has been developed. The sequential protocol provides a direct access to 4H-pyranonaphthoquinones in moderate to very good yields and good to excellent enantioselectivities at a very low catalyst loading (0.5 mol%) of the squaramide. PMID:26660230

  12. 03219A, a new Δ(8,9)-pregnene isolated from Streptomyces sp. SCSIO 03219 obtained from a South China Sea sediment.

    PubMed

    Zhang, Yun; Zhou, Xiao; Huang, Hongbo; Tian, Xinpeng; Song, Yongxiang; Zhang, Si; Ju, Jianhua

    2013-06-01

    03219A (1), a new pregnene steroid possessing a rare Δ(8,9)-double bond in the skeleton, together with the known naphthoquinone antibiotic (+)-cryptosporin (2) have been isolated from the fermentation broth of Streptomyces sp. SCSIO 03219, which was isolated from a marine sediment collected in the South China Sea. The structure of 03219A was elucidated using a combination of NMR, MS and X-ray crystallographic methods.

  13. Determination of glucosamine and carisoprodol in pharmaceutical formulations by LC with pre-column derivatization and UV detection.

    PubMed

    Hadad, Ghada M; Abdel-Salam, Randa A; Emara, Samy

    2012-04-01

    A simple and reliable precolumn derivatization liquid chromatography method with ultraviolet detection has been developed and validated for the analysis of glucosamine (GS) in various dietary supplement formulations and raw materials. Additionally, the proposed method was used for analysis of carisoprodol (CR) found in ternary mixture with paracetamol (PR) and caffeine (CF). The linearity ranges were 1-100 μg/mL for GS, 1-150 μg/mL for CR, PR and CF. Derivatization was used with 1,2-naphthoquinone-4-sulphonic acid sodium salt in the presence of borate buffer. Chromatographic separation of GS-naphthoquinone derivative was achieved by using a mixture of acetonitrile and water (pH 7.3 adjusted with 0.1 M NaOH) in the ratio 10:90, v/v and flow-rate of 1.0 mL/min. UV detection was carried out at 280 nm. For PR, CF, and CR-naphthoquinone derivative, the chromatographic separation was achieved by using mixture of acetonitrile and 20 mM KH(2)PO(4) (pH 3.0 adjusted with phosphoric acid) in the ratio 20:80, v/v and flow-rate of 1.0 mL/min. UV detection was carried out at 275 nm. The limits of detection were 37.2, 35.9, 30.4 and 40.0 ng/mL for GS, CR, PR and CF, respectively. PMID:22362883

  14. Inhibitors of human immunodeficiency virus integrase.

    PubMed Central

    Fesen, M R; Kohn, K W; Leteurtre, F; Pommier, Y

    1993-01-01

    In an effort to further extend the number of targets for development of antiretroviral agents, we have used an in vitro integrase assay to investigate a variety of chemicals, including topoisomerase inhibitors, antimalarial agents, DNA binders, naphthoquinones, the flavone quercetin, and caffeic acid phenethyl ester as potential human immunodeficiency virus type 1 integrase inhibitors. Our results show that although several topoisomerase inhibitors--including doxorubicin, mitoxantrone, ellipticines, and quercetin--are potent integrase inhibitors, other topoisomerase inhibitors--such as amsacrine, etoposide, teniposide, and camptothecin--are inactive. Other intercalators, such as chloroquine and the bifunctional intercalator ditercalinium, are also active. However, DNA binding does not correlate closely with integrase inhibition. The intercalator 9-aminoacridine and the polyamine DNA minor-groove binders spermine, spermidine, and distamycin have no effect, whereas the non-DNA binders primaquine, 5,8-dihydroxy-1,4-naphthoquinone, and caffeic acid phenethyl ester inhibit the integrase. Caffeic acid phenethyl ester was the only compound that inhibited the integration step to a substantially greater degree than the initial cleavage step of the enzyme. A model of 5,8-dihydroxy-1,4-naphthoquinone interaction with the zinc finger region of the retroviral integrase protein is proposed. Images Fig. 2 PMID:8460151

  15. [Multi-component quantitative analysis combined with chromatographic fingerprint for quality assessment of Onosma hookeri].

    PubMed

    Aga, Er-bu; Nie, Li-juan; Dongzhi, Zhuo-ma; Wang, Ju-le

    2015-11-01

    A method for simultaneous determination of the shikonin, acetyl shikonin and β, β'-dimethylpropene shikonin in Onosma hookeri and the chromatographic fingerprint was estabished by HPLC-DAD on an Agilent Zorbax SB-column with a gradient elution of acetonitrile and water at 0.8 mL x min(-1), 30 degrees C. The quality assessment was conducted by comparing the content difference of three naphthoquinone constituents, in combination with chromatographic fingerprint analysis and systems cluster analysis among 7 batches of radix O. hookeri. The content of the three naphthoquinone constituents showed wide variations in 7 bathces. The similarity value of the fingerprints of sample 5, 6 and 7 was above 0.99, sample 2 and 3 above 0.97, sample 3 and 4 above 0.90, and other samples larger than 0.8, which was in concert with the content of three naphthoquinone constituents. The 7 samples were roughly divided into 4 categories. The results above indicated that the using of this medicine is complex and rather spotty. The established HPLC fingerprints and the quantitative analysis method can be used efficiently for quality assessment of O. hookeri.

  16. Development of a test system for screening toxic substances: a comparison using organic substances

    SciTech Connect

    Thomas, C.L.

    1985-01-01

    The purpose of this research was to develop a test system for screening toxic substances by predicting their aquatic ecosystem effects. The system studied was a static, one liter microcosm with a diverse species assemblage. The microcosm was composed of biotic inoculum, chemically defined medium and sediment. The biotic inoculum contained primary producers, grazers, carnivores and decomposers. Three different types of sediment were studied: sand, clay, and clay plus sand. Four organic chemicals: phenol, triethylene glycol (TEG), quinoline and naphthoquinone were evaluated with this test system. The toxicities of TEG, quinoline and naphthoquinone were compared for each sediment type. Toxicity was evaluated in terms of the chemical's effects on primary productivity and heterotrophic activity though other effects are also noted. Naphthoquinone concentration exhibited no correlation between ecosystem property values and therefore, could not be ranked. Phenol exhibited the greatest toxicity to net production immediately after the toxicant addition. Quinoline was most toxic to net production over the longer time scale. TEG exhibited the least toxicity to net production, however, TEG exhibited higher toxicity to heterotrophic activity than either quinoline or phenol. Although the type of sediment used in the microcosms did not change the relative toxicities of the chemicals, the microcosms with clay sediment always were observed to exhibit lower net production and higher variability.

  17. Oxidative protein modification as predigestive mechanism of the carnivorous plant Dionaea muscipula: an hypothesis based on in vitro experiments.

    PubMed

    Galek, H; Osswald, W F; Elstner, E F

    1990-01-01

    Aqueous leaf extracts from Dionaea muscipula contain quinones such as the naphthoquinone plumbagin that couple to different NADH-dependent diaphorases, producing superoxide and hydrogen peroxide upon autoxidation. Upon preincubation of Dionaea extracts with certain diaphorases and NADH in the presence of serumalbumin (SA), subsequent tryptic digestion of SA is facilitated. Since the secretroy glands of Droseracea contain proteases and possibly other degradative enzymes it is suggested that the presence of oxygen-activating redox cofactors in the extracts function as extracellular predigestive oxidants which render membrane-bound proteins of the prey (insects) more susceptible to proteolytic attacks.

  18. Bioactive compounds from the endophytic fungus Fusarium proliferatum.

    PubMed

    Dame, Zerihun T; Silima, Beauty; Gryzenhout, Marieka; van Ree, Teunis

    2016-06-01

    The crude extract of an endophytic fungus isolated from Syzygium cordatum and identified as Fusarium proliferatum showed 100% cytotoxicity against the brine shrimp Artemia salina at 100 μg/mL. Seven coloured, biologically active metabolites - including ergosta-5,7,22-trien-3β-ol, nectriafurone-8-methyl ether, 9-O-methyl fusarubin, bostrycoidin, bostrycoidin-9-methyl ether and 8-hydroxy-5,6-dimethoxy-2-methyl-3-(2-oxo-propyl)-1,4-naphthoquinone- were isolated from the extract. PMID:26158312

  19. Design, synthesis, and biological evaluation of 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones and related compounds as antifungal and antibacterial agents.

    PubMed

    Tandon, Vishnu K; Yadav, Dharmendra B; Maurya, Hardesh K; Chaturvedi, Ashok K; Shukla, Praveen K

    2006-09-01

    A series of (S)-N-(3-chloro-1,4-naphthoquinon-2-yl)-alpha-amino acid ethyl esters 3 and 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones 6-23 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationship of these compounds was studied and the results show that the compounds 3a and 3b exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii whereas compounds 12 and 22 showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli.

  20. Bilayer resist system utilizing alkali-developable organosilicon positive photoresist

    NASA Astrophysics Data System (ADS)

    Nate, Kazuo; Mizushima, Akiko; Sugiyama, Hisashi

    1991-06-01

    A bi-layer resist system utilizing an alkali-developable organosilicon positive photoresist (OSPR) has been developed. The composite prepared from an alkali-soluble organosilicon polymer, poly(p- hydroxybenzylsilsesquioxane) and naphthoquinone diazide becomes a alkali-developable positive photoresist which is sensitive to UV (i line - g line) region, and exhibited high oxygen reactive ion etching (O2 RIE) resistance. The sensitivity and the resolution of OSPR are almost the same as those of conventional novolac-based positive photoresists. The bi-layer resist system utilizing OSPR as the top imaging layer gave fine patterns of underlayers with high aspect ratio easily.

  1. All optical switching in henna thin film

    NASA Astrophysics Data System (ADS)

    Henari, Fryad Z.; Jasim, Khalil E.

    2013-08-01

    The optical nonlinearity in henna (Lawson (2- hydroxyl-1,4 naphthoquinone) film was utilized to demonstrate all optical switching. The nonlinear absorption of the henna film was calculated by measuring the transmission of the laser beam ( λ = 488 nm) as a function of incident light intensities. The observed nonlinear absorption is attributed to a two-photon absorption process. The pump and probe technique was used to demonstrate all optical switching. The switching characteristics can be utilized to generate all-optical logic gates such as simple inverter switches (NOT) NOR, AND NAND logic functions.

  2. Determination of the Juglone Content of Juglans regia Leaves by GC/MS.

    PubMed

    Matławska, Irena; Bylka, Wiesława; Widy-Tyszkiewicz, Ewa; Stanisz, Beata

    2015-07-01

    The constituents of walnut (Juglans regia L.) leaves are represented by tannins, phenolics, and naphthoquinones, the characteristic compound being juglone. The content of juglone in the methanolic extract of the leaves determined by the GC/MS method was 9.9 ± 0.2 mg/100 g; small amounts (1.3 ± 0.02 mg/100 g) were recorded in the infusion, whereas in the decoction it was not detected. As some studies indicate toxicity of juglone, only decoctions should be recommended for therapeutic use.

  3. Formation of nanotunnels inside a resist film in laser interference lithography.

    PubMed

    Wei, Qi; Hu, Fanhua; Wang, Liyuan

    2015-05-19

    A few kinds of 2-diazo-1-naphthoquinone-4-sulfonates of poly(4-hydroxylstyrene) were prepared to form one-component i-line photoresists. In the laser interference lithography experiments of some of the photoresists, nanotunnels were observed to be aligned in the interior of the resist film. The shape and size of the nanotunnels remain virtually unchanged even under an increased exposure dose, indicating that the exposure energy is confined within the tunnel space. The formation of the nanotunnels results from the effect of standing waves and the permeation of developer from the surface deep into the resist films. PMID:25938301

  4. Contribution of reductase activity to quinone toxicity in three kinds of hepatic cells.

    PubMed

    Ishihara, Yasuhiro; Tsuji, Kaori; Ishii, Satomi; Kashiwagi, Kyoko; Shimamoto, Norio

    2012-01-01

    Two mechanisms have been proposed to explain quinone cytotoxicity: oxidative stress via the redox cycle, and the arylation of intracellular nucleophiles. The redox cycle is catalyzed by intracellular reductases, and therefore the toxicity of redox cycling quinone is considered to be closely associated with the reductase activity. This study examined the relationship between quinone toxicity and the intracellular reductase activity using 3 kinds of hepatic cells; rat primary hepatocytes, HepG2 and H4IIE. The intracellular reductase activity was; primary hepatocyte >HepG2>H4IIE. The three kinds of cells showed almost the same vulnerability to an arylating quinone, 1,4-naphthoquinone (NQ). However, the susceptibility to a redox cycling quinone, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) was; primary hepatocyte>HepG2>H4IIE. In addition, the cytotoxicity elicited by DMNQ was significantly attenuated in HepG2 cells and almost completely suppressed in primary hepatocytes by diphenyleneiodonium chloride, a reductase inhibitor. These data suggest that cells with a high reductase activity are susceptible to redox cycling quinones. This study provides essential evidence to assess the toxicity of quinone-based drugs during their developmental processes.

  5. Improved understanding of bimolecular reactions in deceptively simple homogeneous media: From laboratory experiments to Lagrangian quantification

    NASA Astrophysics Data System (ADS)

    Zhang, Yong; Qian, Jiazhong; Papelis, Charalambos; Sun, Pengtao; Yu, Zhongbo

    2014-02-01

    Medium heterogeneity affects reaction kinetics by controlling the mixing of reactant particles, but the linkage between medium properties and reaction kinetics is difficult to build, even for simple, relatively homogeneous media. This study aims to explore the dynamics of bimolecular reactions, aniline + 1,2-naphthoquinone-4-sulfonic acid → 1,2-naphthoquinone-4-aminobenzene, in relatively homogeneous flow cells. Laboratory experiments were conducted to monitor the transport of both conservative and reactive tracers through columns packed with silica sand of specific diameters. The measured tracer breakthrough curves exhibit subdiffusive behavior with a late-time tail becoming more pronounced with decreasing sand size, probably due to the segregated flow regions formed more easily in columns packed with smaller size sand. Numerical analysis using a novel Lagrangian model shows that subdiffusion has a twofold effect on bimolecular reactions. While subdiffusion enhances the power-law growth rate of product mass by prolonging the exposure of reactant particles in the depletion zone, the global reaction rate is constrained because subdiffusion constrains the mobility of reactant particles. Reactive kinetics in deceptively simple homogeneous media is therefore controlled by subdiffusion, which is sensitive to the dimensions of packed sand.

  6. Lewis Acids as Activators in CBS-Catalysed Diels-Alder Reactions: Distortion Induced Lewis Acidity Enhancement of SnCl4.

    PubMed

    Nödling, Alexander R; Möckel, Robert; Tonner, Ralf; Hilt, Gerhard

    2016-09-01

    The effect of several Lewis acids on the CBS catalyst (named after Corey, Bakshi and Shibata) was investigated in this study. While (2) H NMR spectroscopic measurements served as gauge for the activation capability of the Lewis acids, in situ FT-IR spectroscopy was employed to assess the catalytic activity of the Lewis acid oxazaborolidine complexes. A correlation was found between the Δδ((2) H) values and rate constants kDA , which indicates a direct translation of Lewis acidity into reactivity of the Lewis acid-CBS complexes. Unexpectedly, a significant deviation was found for SnCl4 as Lewis acid. The SnCl4 -CBS adduct was much more reactive than the Δδ((2) H) values predicted and gave similar reaction rates to those observed for the prominent AlBr3 -CBS adduct. To rationalize these results, quantum mechanical calculations were performed. The frontier molecular orbital approach was applied and a good correlation between the LUMO energies of the Lewis acid-CBS-naphthoquinone adducts and kDA could be found. For the SnCl4 -CBS-naphthoquinone adduct an unusual distortion was observed leading to an enhanced Lewis acidity. Energy decomposition analysis with natural orbitals for chemical valence (EDA-NOCV) calculations revealed the relevant interactions and activation mode of SnCl4 as Lewis acid in Diels-Alder reactions. PMID:27492791

  7. Pigment Cell Differentiation in Sea Urchin Blastula-Derived Primary Cell Cultures

    PubMed Central

    Ageenko, Natalya V.; Kiselev, Konstantin V.; Dmitrenok, Pavel S.; Odintsova, Nelly A.

    2014-01-01

    The quinone pigments of sea urchins, specifically echinochrome and spinochromes, are known for their effective antioxidant, antibacterial, antifungal, and antitumor activities. We developed in vitro technology for inducing pigment differentiation in cell culture. The intensification of the pigment differentiation was accompanied by a simultaneous decrease in cell proliferation. The number of pigment cells was two-fold higher in the cells cultivated in the coelomic fluids of injured sea urchins than in those intact. The possible roles of the specific components of the coelomic fluids in the pigment differentiation process and the quantitative measurement of the production of naphthoquinone pigments during cultivation were examined by MALDI and electrospray ionization mass spectrometry. Echinochrome A and spinochrome E were produced by the cultivated cells of the sand dollar Scaphechinus mirabilis in all tested media, while only spinochromes were found in the cultivated cells of another sea urchin, Strongylocentrotus intermedius. The expression of genes associated with the induction of pigment differentiation was increased in cells cultivated in the presence of shikimic acid, a precursor of naphthoquinone pigments. Our results should contribute to the development of new techniques in marine biotechnology, including the generation of cell cultures producing complex bioactive compounds with therapeutic potential. PMID:24979272

  8. Single crystal X-ray structure of Lawsone anion: Evidence for coordination of alkali metal ions and formation of naphthosemiquinone radical in basic media

    NASA Astrophysics Data System (ADS)

    Salunke-Gawali, Sunita; Kathawate, Laxmi; Shinde, Yogesh; Puranik, Vedavati G.; Weyhermüller, Thomas

    2012-02-01

    2-hydroxy-1,4-naphthoquinone; Lawsone (Lw) is a natural compound found in henna leaves. The reaction of lawsone with 'Na' metal (Lw-1), CH3COONa (Lw-2), NaOH (Lw-3), KOH (Lw-4), K2CO3 (Lw-5) and Tris(hydroxymethyl)aminomethane (Lw-6) were studied. Red orange solids obtained for Lw-1 to Lw-6 are characterized by Elemental Analysis, FTIR, 1HNMR and EPR studies. The results reveal the coordination of alkali metals 'Na' and 'K' to lawsone anion. The single crystal X-ray structure of Lw-6 was solved and it crystallizes in triclinic space group P-1 with extensive hydrogen bonding network of Csbnd H⋯O, Nsbnd H⋯O and Osbnd H⋯O between cations and anions. Polycrystalline powder X-band EPR spectra of Lw-1 to Lw-5 shows signals ˜2.004 at 133 K, while Lw-6 is EPR silent. The naphthosemiquinone (NSQ-rad ) radical formed in Lw-2 to Lw-5, is due to disproportion reaction of catechol and naphthoquinone.

  9. Naphthazarin has a protective effect on the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson's disease model.

    PubMed

    Choi, Seon Young; Son, Tae Gen; Park, Hee Ra; Jang, Young Jung; Oh, Shin Bi; Jin, Bora; Lee, Jaewon

    2012-09-01

    "Neurohormesis" refers to a response to a moderate level of stress that enhances the ability of the nervous systems to resist more severe stress that might be lethal or cause dysfunction or disease. Neurohormetic phytochemicals, such as, resveratrol, sulforaphane, curcumin, and catechins, protect neurons against injury and disease. Naphthoquinones, such as, juglone and plumbagin, induce robust hormetic stress responses. However, the possibility that subtoxic dose of 5,8-dihydroxy-1,4-naphthoquinone (naphthazarin) may protect against brain diseases via the activation of an adaptive stress response pathway in the brain has not been investigated. In this study, we examined the neurohormetic effect of a subtoxic dose of naphthazarin in a Parkinson's disease model. It was found that, under these conditions, naphthazarin enhanced movement ability, prevented loss of dopaminergic neurons, and attenuated neuroinflammation in a 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson's disease model. Furthermore, it was found that the neuroprotective effect of naphthazarin was mediated by the suppression of astroglial activation in response to 1-methyl-4-phenylpyridine treatment. In conclusion, we suggest that naphthazarin, in view of its hormetic effect on neuroprotection, be viewed as a potential treatment for Parkinson's disease and other neurodegenerative diseases associated with neuroinflammation.

  10. New Aminonaphthoquinone from the Sea Urchins Strongylocentrotus pallidus and Mesocentrotus nudus.

    PubMed

    Vasileva, Elena A; Mishchenko, Natalia P; Zadorozhny, Pavel A; Fedoreyev, Sergey A

    2016-06-01

    The aminonaphthoquinone, spinamine E (5), was isolated for the first time from the sea urchins Strongylocentrotus pallidus (Sars G.O., 1872) and Mesocentrotus nudus (A. Agassiz, 1864). The structure of 5 was elucidated as 2-amino-3,5,6,7,8-pentahydroxy-1,4-naphthoquinone using ID 1H-, 13C- and 2D NMR procedures, and HR-ESI mass-spectrometric data of 5 and its trimethyl ether. Spinamine E, as well as two other aminonaphthoquinones of sea urchins, echinamines A (2) and B (3), along with their hydroxylated analogues, spinochrome E (4) and echinochrome A (1), were tested for their ability to scavenge the stable DPPH radical and to inhibit lipid peroxidation. All investigated naphthoquinones obtained from the sea urchins showed a high antiradical activity, which was up to 1.5 times higher than that of α-tocopherol. Echinamine B showed the highest scavenging effect (EC50 = 6.5-10(-6) M); this effect decreases in the series 3>5>1>2>4>α-tocopherol. In a lipid peroxidation inhibition testing model, echinamine B and spinamine E showed the highest inhibitory effect. The stability of compounds 1-5 in weakly alkaline solutions was evaluated. PMID:27534126

  11. Antioxidant properties, autooxidation, and mutagenic activity of echinochrome a compared with its etherified derivative.

    PubMed

    Lebedev, A V; Levitskaya, E L; Tikhonova, E V; Ivanova, M V

    2001-08-01

    Antioxidant properties of 2,3,5,7,8-pentahydroxy-6-ethyl-1,4-naphthoquinone (echinochrome A) were linked with the scavenging of peroxy radicals in liposomes, trapping of superoxide anion radicals, and binding of ferrous ions to inactive complexes in the aqueous phase. The antioxidant property of 6-ethyl-2,3,7-trimethoxy-5,8-dihydroxy-1,4-naphthoquinone (trimethoxyechinochrome A) was negligible. Autooxidation of echinochrome A was increased in basic media according to the degree of its dissociation. Autooxidation of polyvalent anions in basic media was accompanied by generation of naphthosemiquinone and superoxide anion radicals as free radical intermediates. An increased rate of echinochrome A autooxidation was noted in the presence of calcium ions. This was explained by a shift of pK of Ca2+-echinochrome A complexes toward acidic pH comparably with echinochrome A. Echinochrome A possessed pronounced mutagenic activity, while trimethoxyechinochrome A was inactive in the Salmonella/mammalian microsome reverse mutation assay (Ames test) for all examined cells (TA98, TA100, TA1537). Comparison of the chemical and biological activity of echinochrome A and trimethoxyechinochrome A demonstrated the key role of the beta-hydroxyl groups in the 2nd, 3rd, and 7th naphthol cycle positions. The O2-* and naphthosemiquinone radicals generated in the redox transition of 2,3-oxygroups may be the reason for the strongly pronounced mutagenicity of echinochrome A. PMID:11566058

  12. Mutagenic activity of isoxazolylnaphthoquinoneimines assayed by micronucleus bone marrow test.

    PubMed

    Sicardi, S M; Ferrato, E

    1995-05-01

    Studies were undertaken to evaluate the ability of various quinoneimines to induce micronuclei in bone marrow cells as a measure of their genotoxicity. Accordingly, 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (I), its 2-acetyl derivative (II) and 2-[(5-methyl-3-isoxazolyl)amino]-N-(5-methyl-3-isoxazolyl)-1 ,4- naphthoquinone-4-imine (III), as well as two of their precursors, 2-hydroxynaphthoquinone (NQ-2-OH) and 3,4-dimethyl-5-aminoisoxazole (DMAI) were given by intraperitoneal injection at 5, 50, 100 and 200 mg/Kg doses to S.J.L. Swiss mice with 24 h sampling time. Compounds I and II displayed highly significant differences at 50, 100 and 200 mg/kg doses (p < 0.01) and their mutagenic dose response curves correlated closely with an inverted U-shaped form whose interpretation is still the subject of controversy. NQ-2-OH only produced a significant increase in micronucleus frequency at 50 mg/kg, whereas no mutagenic activity was found for compound III and DMAI at the doses assayed. At 50 mg/kg the order of relative mutagenic potencies was I > II > NQ-2-OH. Mechanisms advanced to explain loss of drug activity at high doses include capture saturation, enzymatic induction during metabolism and participation of an independent defense system. PMID:7753107

  13. [Preparation and application of the quinonyl chloromethylation polystyrene in biological treatment of wastewater].

    PubMed

    Zhang, Hua-Yu; Xu, Qing; Niu, Chun-Mei; Wang, Ya-Jun; Hou, Zheng-Hao; Li, Shao-Ying; Chen, Yan-Ming; Lian, Jing; Wu, Shi-Bin; Guo, Jian-Bo

    2014-05-01

    The technology of non-water-soluble mediator anaerobic biological catalysis has attracted more and more attention in the field of environment technology. In this study, five kinds of quinonly compounds were grafted on the chloromethylation polystyrene macromolecular carrier by Friedel-Crafts reaction. Reaction factors of temperature and molar ratio for the 1,4-naphthoquinone grafting carrier were optimized, and the optimal temperature was 78 degreesC while the optimal molar ratio of 1, 4-naphthoquinone and chloromethylation polystyrene was 2: 1. Fourier infrared spectrum analysis confirmed that the quinone groups were successfully grafted on the macromolecular backbone chloromethylation polystyrene. Catalysis using the five kinds of quinonly materials as non-water-soluble redox mediators enhanced the biological denitrification rate and the decoloration of azo dyes, meanwhile these materials showed good reusability in the biodegradation of azo dye. This study developed a new method for the preparation of quinonly materials and revealed a new field in the technology of mediator catalysis.

  14. Reaction mechanism of naphthyl radicals with molecular oxygen. 1. Theoretical study of the potential energy surface.

    PubMed

    Zhou, Chong-Wen; Kislov, Vadim V; Mebel, Alexander M

    2012-02-16

    Potential energy surfaces (PESs) of the reactions of 1- and 2-naphthyl radicals with molecular oxygen have been investigated at the G3(MP2,CC)//B3LYP/6-311G** level of theory. Both reactions are shown to be initiated by barrierless addition of O(2) to the respective radical sites of C(10)H(7). The end-on O(2) addition leading to 1- and 2-naphthylperoxy radicals exothermic by 45-46 kcal/mol is found to be more preferable thermodynamically than the side-on addition. At the subsequent reaction step, the chemically activated 1- and 2-C(10)H(7)OO adducts can eliminate an oxygen atom leading to the formation of 1- and 2-naphthoxy radical products, respectively, which in turn can undergo unimolecular decomposition producing indenyl radical + CO via the barriers of 57.8 and 48.3 kcal/mol and with total reaction endothermicities of 14.5 and 10.2 kcal/mol, respectively. Alternatively, the initial reaction adducts can feature an oxygen atom insertion into the attacked C(6) ring leading to bicyclic intermediates a10 and a10' (from 1-naphthyl + O(2)) or b10 and b10' (from 2-naphthyl + O(2)) composed from two fused six-member C(6) and seven-member C(6)O rings. Next, a10 and a10' are predicted to decompose to C(9)H(7) (indenyl) + CO(2), 1,2-C(10)H(6)O(2) (1,2-naphthoquinone) + H, and 1-C(9)H(7)O (1-benzopyranyl) + CO, whereas b10 and b10' would dissociate to C(9)H(7) (indenyl) + CO(2), 2-C(9)H(7)O (2-benzopyranyl) + CO, and 1,2-C(10)H(6)O(2) (1,2-naphthoquinone) + H. On the basis of this, the 1-naphthyl + O(2) reaction is concluded to form the following products (with the overall reaction energies given in parentheses): 1-naphthoxy + O (-15.5 kcal/mol), indenyl + CO(2) (-123.9 kcal/mol), 1-benzopyranyl + CO (-97.2 kcal/mol), and 1,2-naphthoquinone + H (-63.5 kcal/mol). The 2-naphthyl + O(2) reaction is predicted to produce 2-naphthoxy + O (-10.9 kcal/mol), indenyl + CO(2) (-123.7 kcal/mol), 2-benzopyranyl + CO (-90.7 kcal/mol), and 1,2-naphthoquinone + H (-63.2 kcal

  15. A mechanistic examination of redox cycling activity in carbonaceous particulate matter

    NASA Astrophysics Data System (ADS)

    McWhinney, Robert David

    Mechanistic aspects of carbonaceous aerosol toxicity were examined with respect to the ability of particles to catalyse reactive oxygen species-generating redox cycling reactions. To investigate the role of secondary organic material, we examined two systems. In the first, two-stroke engine exhaust particles were found to increase their ability to catalyse redox cycling in the presence of a reducing agent, dithiothreitol (DTT), when the exhaust was exposed to ozone. This occurred through deposition of redox-active secondary organic aerosol (SOA) onto the particle that was ten times more redox active per microgram than the primary engine particle. In the second system, naphthalene SOA formed highly redox active particles. Activity was strongly correlated to the amount of the 1,4- and 1,2-naphthoquinone measured in the particle phase. However, these species and the newly quantified naphthalene oxidation product 5-hydroxy-1,4-naphthoquinone accounted for only 30% of the observed DTT decay from the particles. Gas-particle partitioning coefficients suggest 1,4- and 1,2- naphthoquinone are not strong contributors to ambient particle redox activity at 25 °C. However, a large number of redox active species are unidentified. Some of these may be highly oxidised products of sufficiently low vapour pressure to be atmospherically relevant. DTT activity of diesel particles was found to be high per unit mass. The activity was found to be associated with the insoluble fraction as filtration of the particles nearly eliminated DTT decay. Neither methanol nor dichloromethane extracts of diesel particles exhibited redox activity, indicating that the redox active species are associated with the black carbon portion of the particles. Examination of particle concentration techniques found that use of water condensation to grow and concentrate particles introduced a large organic artefact to the particles. Experiments with concentrated inorganic particles suggest that the source of this

  16. Interactions between manganese oxides and multiple-ringed aromatic compounds

    SciTech Connect

    Whelan, G.; Sims, R.C.

    1992-08-01

    Objective is to determine whether Mn reductive dissolution can oxidize multiple-ringed aromatics, such as PAHs, in an oxic environment? Research indicated that certain PAHs (eg, dihydrodiols and diones that form free-radical intermediates) are susceptible to oxidation and polymerization. Over 14 days, 83, 76, 54, 70, and 20% of the Mn was reduced by 2,3-, 1,3-, and 1,4-naphthalenediol, quinizarin, and 1,4-naphthoquinone, respectively. 100, 100, and 65% of the first three PAHs were oxidized, respectively. Aromatics with diol functional groups were more easily oxidized than those with only dione groups. Relatively insoluble compounds like quinizarin can be oxidized; insoluble ``humic-like`` material precipitated, indicating a polymerization-humification process. Results suggest that electron transfer/organic release from the oxide surface is the rate-limiting step.

  17. Interactions between manganese oxides and multiple-ringed aromatic compounds

    SciTech Connect

    Whelan, G. ); Sims, R.C. . Dept. of Civil and Environmental Engineering)

    1992-08-01

    Objective is to determine whether Mn reductive dissolution can oxidize multiple-ringed aromatics, such as PAHs, in an oxic environment Research indicated that certain PAHs (eg, dihydrodiols and diones that form free-radical intermediates) are susceptible to oxidation and polymerization. Over 14 days, 83, 76, 54, 70, and 20% of the Mn was reduced by 2,3-, 1,3-, and 1,4-naphthalenediol, quinizarin, and 1,4-naphthoquinone, respectively. 100, 100, and 65% of the first three PAHs were oxidized, respectively. Aromatics with diol functional groups were more easily oxidized than those with only dione groups. Relatively insoluble compounds like quinizarin can be oxidized; insoluble ''humic-like'' material precipitated, indicating a polymerization-humification process. Results suggest that electron transfer/organic release from the oxide surface is the rate-limiting step.

  18. Inhibitors of the mitochondrial cytochrome b-c1 complex inhibit the cyanide-insensitive respiration of Trypanosoma brucei.

    PubMed

    Turrens, J F; Bickar, D; Lehninger, A L

    1986-06-01

    The cyanide-insensitive respiration of bloodstream trypomastigote forms of Trypanosoma brucei (75 +/- 8 nmol O2 min-1(mg protein)-1) is completely inhibited by the mitochondrial ubiquinone-like inhibitors 2-hydroxy-3-undecyl-1,4-naphthoquinone (UHNQ) and 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT). The Ki values for UHDBT (30 nM) and UHNQ (2 microM) are much lower than the reported Ki for salicylhydroxamic acid (SHAM) (5 microM), a widely used inhibitor of the cyanide-insensitive oxidase. UHNQ also stimulated the glycerol-3-phosphate-dependent reduction of phenazine methosulfate, demonstrating that the site of UHNQ inhibition is on the terminal oxidase of the cyanide-insensitive respiration of T. brucei. These results suggest that a ubiquinone-like compound may act as an electron carrier between the two enzymatic components of the cyanide-insensitive glycerol-3-phosphate oxidase.

  19. Proteomic Analysis of the Antibacterial Mechanism of Action of Juglone against Staphylococcus aureus.

    PubMed

    Wang, Jiayi; Wang, Zixue; Wu, Rina; Jiang, Donghua; Bai, Bing; Tan, Dehong; Yan, Tingcai; Sun, Xiyun; Zhang, Qi; Wu, Zhaoxia

    2016-06-01

    Juglone is a plant-derived 1,4-naphthoquinone with confirmed antibacterial activity. However, the mechanism of action of juglone against Staphylococcus aureus remains unclear. Possible mechanisms were explored by a proteomic analysis of S. aureus proteins that are inhibited by juglone. Two-dimensional gel electrophoresis revealed that 21 protein spots were differentially expressed between juglone-treated and untreated cells of which 13 were identified. A bioinformatic analysis revealed that proteins participating in protein synthesis, the tricarboxylic acid cycle, as well as DNA and RNA synthesis were inhibited by juglone, thus leading to cell collapse. These findings provide clues regarding the mechanism of action of juglone, which can be effective for treating cases of S. aureus infection.

  20. Naphthazarin protects against glutamate-induced neuronal death via activation of the Nrf2/ARE pathway

    SciTech Connect

    Son, Tae Gen; Kawamoto, Elisa M.; Yu, Qian-Sheng; Greig, Nigel H.; Mattson, Mark P.; Camandola, Simonetta

    2013-04-19

    Highlights: •Naphthazarin activates the Nrf2/ARE pathway. •Naphthazarin induces Nrf2-driven genes in neurons and astrocytes. •Naphthazarin protects neurons against excitotoxicity. -- Abstract: Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. We previously screened several natural phytochemicals and identified plumbagin as a novel activator of the Nrf2/ARE pathway that can protect neurons against ischemic injury. Here we extended our studies to natural and synthetic derivatives of plumbagin. We found that 5,8-dimethoxy-1,4-naphthoquinone (naphthazarin) is a potent activator of the Nrf2/ARE pathway, up-regulates the expression of Nrf2-driven genes in primary neuronal and glial cultures, and protects neurons against glutamate-induced excitotoxicity.

  1. Screening and determination of potential xanthine oxidase inhibitors from Radix Salviae Miltiorrhizae using ultrafiltration liquid chromatography-mass spectrometry.

    PubMed

    Liu, Yang; Liu, Shu; Liu, Zhiqiang

    2013-04-01

    Xanthine oxidase (XOD) inhibitors play an important role in the treatment of gout and many other diseases related to the superoxide anion metabolism. In this study, an ultrafiltration-liquid chromatography-mass spectrometry (UF-LC-MS) method was developed for the screening and identification of potential XOD inhibitors from Radix Salviae Miltiorrhizae extract. Eleven lipophilic diterpenoid quinines were identified as XOD inhibitors from the extract. The relationship between the structure and activity of the detected compounds was estimated on the basis of the UF-LC-MS data. The results demonstrate that the 1,2-naphthoquinone group is necessary for the XOD inhibitory activity of the compounds, and that furan and hydroxyl on the alicyclic ring could enhance the activity of the compounds at different levels. These results may explain and support the medical use of the extract of Radix S. Miltiorrhizae for the prevention and treatment of hyperuricemia and gout.

  2. Ecofriendly syntheses of phenothiazones and related structures facilitated by laccase – A comparative study

    DOE PAGESBeta

    Cannatelli, Mark D.; Ragauskas, Arthur J.

    2016-07-06

    The biocatalytic synthesis of phenothiazones and related compounds has been achieved in an aqueous system under mild conditions facilitated by laccase oxidation. It was found that by coupling 2-aminothiophenol directly with 1,4-quinones, the product yields could be significantly increased compared to generating the 1,4-quinones in situ from the corresponding hydroquinones via laccase oxidation. However, laccase still proved to be pivotal for achieving highest product yields by catalyzing the final oxidation step. Furthermore, a difference in reactivity of aromatic and aliphatic amines toward 1,4-naphthoquinone is observed. Furthermore, this study provides a sustainable approach to the synthesis of a biologically important classmore » of compounds.« less

  3. 2-Phenylaminonaphthoquinones and related compounds: synthesis, trypanocidal and cytotoxic activities.

    PubMed

    Sieveking, Ivan; Thomas, Pablo; Estévez, Juan C; Quiñones, Natalia; Cuéllar, Mauricio A; Villena, Juan; Espinosa-Bustos, Christian; Fierro, Angélica; Tapia, Ricardo A; Maya, Juan D; López-Muñoz, Rodrigo; Cassels, Bruce K; Estévez, Ramon J; Salas, Cristian O

    2014-09-01

    A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds.

  4. Photogenerated radical intermediates of vitamin K 1: a time-resolved resonance Raman study

    NASA Astrophysics Data System (ADS)

    Balakrishnan, G.; Umapathy, S.

    1999-01-01

    Quinones play a vital role in the process of electron transfer in bacterial photosynthetic reaction centers. It is of interest to investigate the photochemical reactions involving quinones with a view to elucidating the structure-function relationships in the biological processes. Resonance Raman spectra of radical anions and the time-resolved resonance Raman spectra of vitamin K 1 (model compound for Q A in Rhodopseudomonas viridis, a bacterial photosynthetic reception center) are presented. The photochemical intermediates of vitamin K 1, viz. radical anion, ketyl radical and o-quinone methide have been identified. The vibrational assignments of all these intermediates are made on the basis of comparison with our earlier TR3 studies on radical anions of naphthoquinone and menaquinone.

  5. Antimalarial efficacy of dynamic compound of plumbagin chemical constituent from Plumbago zeylanica Linn (Plumbaginaceae) against the malarial vector Anopheles stephensi Liston (Diptera: Culicidae).

    PubMed

    Pradeepa, Venkatraman; Sathish-Narayanan, Subbiah; Kirubakaran, Suyambulingam Arunachalam; Senthil-Nathan, Sengottayan

    2014-08-01

    In the present investigation, the effective root compound of plumbagin of Plumbago zeylanica (Plumbaginaceae) was evaluated for chemical constituent and antimalarial effect against the fourth instar larvae of Anopheles stephensi Liston (Diptera). In the chromatographic analyses of root compound with Rf value of 0.788 and NMR analyses also revealed that the effective compound contain naphthoquinone plumbagin were identified as the major chemical constituent. Larval mortality was observed after 3 h of exposure period. The plumbagin compound showed remarkable larvicidal activity against A. stephensi (LC50 32.65 and LC9072.27 ppm). Histopathological effects of compound was observed in the treated larvae. Based on the results, the plumbagin compound of P. zeylanica can be considered as a new source of natural larvicide for the control of malarial vector.

  6. Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II).

    PubMed

    Jayatunga, Madura K P; Thompson, Sam; McKee, Tawnya C; Chan, Mun Chiang; Reece, Kelie M; Hardy, Adam P; Sekirnik, Rok; Seden, Peter T; Cook, Kristina M; McMahon, James B; Figg, William D; Schofield, Christopher J; Hamilton, Andrew D

    2015-04-13

    Protein-protein interactions between the hypoxia inducible factor (HIF) and the transcriptional coactivators p300/CBP are potential cancer targets due to their role in the hypoxic response. A natural product based screen led to the identification of indandione and benzoquinone derivatives that reduce the tight interaction between a HIF-1α fragment and the CH1 domain of p300. The indandione derivatives were shown to fragment to give ninhydrin, which was identified as the active species. Both the naphthoquinones and ninhydrin were observed to induce Zn(II) ejection from p300 and the catalytic domain of the histone demethylase KDM4A. Together with previous reports on the effects of related compounds on HIF-1α and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds. PMID:25023609

  7. A Novel Silicon-Containing Resist For A Bi-Layer Resist System

    NASA Astrophysics Data System (ADS)

    Noguchi, Tsutomu; Nito, Keiichi; Seto, Jun'etsu; Hata, Izumi; Sato, Hiroshi; Tsumori, Toshirou

    1988-01-01

    A new positive working photoresist which is applicable to the bi-layer resist system using a current g-line stepper has been developed. This resist consists of a naphthoquinone diazide photoactive compound and a silicon containing novolak resin, which is synthesised from phenols with siloxane groups(-Si-O-), and formaldehyde by condensation reaction. The Si-containing resist has a resolution capability of 0.5μm L/S with a g-line sensitivity about 250 mJ/cm2, and a high resistance to oxygen plasma, with an etching rate ratio of 61:1(photoresist/Si resist). 0.5μm L/S pattern was precisely transferred to the bottom layer by 02 RIE with vertical side walls.

  8. Synthesis, Photochemical Properties, and Cytotoxicities of 2H-Naphtho[1,2-b]pyran and Its Photodimers.

    PubMed

    Ota, Motohiro; Sasamori, Takahiro; Tokitoh, Norihiro; Onodera, Takefumi; Mizushina, Yoshiyuki; Kuramochi, Kouji; Tsubaki, Kazunori

    2015-06-01

    A 2H-naphtho[1,2-b]pyran, prepared by dimerization of 2-bromo-3-methyl-1,4-naphthoquinone and O-methylation, readily undergoes solid-state [2 + 2] photodimerization to give a photodimer in excellent yield and with excellent selectivity. Retro [2 + 2] cycloaddition can be achieved by irradiation of a solution of the photodimer in chloroform. Interestingly, the 2H-naphtho[1,2-b]pyran dimerizes with a skeletal rearrangement to afford 2,5-dihydro-1-benzoxepin dimers upon irradiation in methanol or via irradiation with hexamethylditin. Furthermore, treatment of the resulting dimers with triethylamine regenerates the 2H-naphtho[1,2-b]pyran monomer. Significant differences in the color, fluorescence, and cytotoxic properties of the monomer and dimers were observed. PMID:25927340

  9. Identification of a cryptic type III polyketide synthase (1,3,6,8-tetrahydroxynaphthalene synthase) from Streptomyces peucetius ATCC 27952.

    PubMed

    Ghimire, Gopal Prasad; Oh, Tae-Jin; Liou, Kwangkyoung; Sohng, Jae Kyung

    2008-10-31

    We identified a 1,134-bp putative type III polyketide synthase from the sequence analysis of Streptomyces peucetius ATCC 27952, named Sp-RppA, which is characterized as 1,3,6,8-tetrahydroxynaphthalene synthase and shares 33% identity with SCO1206 from S. coelicolor A3(2) and 32% identity with RppA from S. griseus. The 1,3,6,8-tetrahydroxynaphthalene synthase is known to catalyze the sequential decarboxylative condensation, intramolecular cyclization, and aromatization of an oligoketide derived from five units of malonyl-CoA to give 1,3,6,8-tetrahydroxynaphthalene, which spontaneously oxidizes to form 2,5,7-trihydroxy-1,4-naphthoquinone (flaviolin). In this study, we report the in vivo expression and in vitro synthesis of flaviolin from purified gene product (Sp-RppA). PMID:18612244

  10. Chemical constituents from the leaves of Juglans mandshurica.

    PubMed

    Yao, Da Lei; Zhang, Chang Hao; Luo, Jie; Jin, Mei; Zheng, Ming Shan; Cui, Jiong Mo; Son, Jong Keun; Li, Gao

    2015-04-01

    Two new (1 and 3) and two known diarylheptanoids (2 and 4), along with two tetralones (5 and 6), one naphthoquinone (7), four phenylpropanoids (8-11), and one phenol (12) were isolated from the leaves of Juglans mandshurica. Their structures were elucidated on the basis of spectral and chemical data. Compounds 2 and 10 are firstly isolated from this plant and 8 and 12 were isolated from the Juglans genus for the first time. Among these compounds, only 7 exhibited moderate cytotoxicities against cultured MGC-803, A549, K562, and HeLa tumor cell lines with IC50 values of 25.90, 28.60, 39.06, 44.90 μM, respectively.

  11. A Soluble, magnesium-independent prenyltransferase catalyzes reverse and regular C-prenylations and O-prenylations of aromatic substrates

    PubMed Central

    Haagen, Yvonne; Unsöld, Inge; Westrich, Lucia; Gust, Bertolt; Richard, Stéphane B.; Noel, Joseph P.; Heide, Lutz

    2010-01-01

    Fnq26 from Streptomyces cinnamonensis DSM 1042 is a new member of the recently identified CloQ/Orf2 class of prenyltransferases. The enzyme was overexpressed in E. coli and purified to apparent homogeneity, resulting in a soluble, monomeric protein of 33.2 kDa. The catalytic activity of Fnq26 is independent of the presence of Mg2+ or other divalent metal ions. With flaviolin (2,5,7-trihydroxy-1,4-naphthoquinone) as substrate, Fnq26 catalyzes the formation of a carbon–carbon-bond between C-3 (rather than C-1) of geranyl diphosphate and C-3 of flaviolin, i.e. an unusual ‘‘reverse’’ prenylation. With 1,3-dihydroxynaphthalene and 4-hydroxybenzoate as substrates Fnq26 catalyzes O-prenylations. PMID:17543953

  12. Novel zinc(II) and copper(II) complexes of a Mannich base derived from lawsone: Synthesis, single crystal X-ray analysis, ab initio density functional theory calculations and vibrational analysis.

    PubMed

    Neves, Amanda P; Vargas, Maria D; Téllez Soto, Claudio A; Ramos, Joanna M; Visentin, Lorenzo do C; Pinheiro, Carlos B; Mangrich, Antônio S; de Rezende, Edivaltrys I P

    2012-08-01

    Zinc(II) and copper(II) complexes of a tridentate Mannich base L1 derived from 2-hydroxy-1,4-naphthoquinone, pyridinecarboxyaldehyde and 2-aminomethylpyridine, [ZnL1Cl(2)]·H(2)O 1 and [CuL1Cl(2)]·2H(2)O 2, have been synthesized and fully characterized. The structure of complex 1 has been elucidated by a single crystal X-ray diffraction study: the zinc atom is pentacoordinate and the coordination geometry is a distorted square base pyramid, with a geometric structural parameter τ equal to 0.149. Vibrational spectroscopy and ab initio DFT calculations of both compounds have confirmed that the two complexes exhibit similar structures. Full assignment of the vibrational spectra was also supported by careful analysis of the distorted geometries generated by the normal modes. PMID:22513170

  13. Onosma L.: A review of phytochemistry and ethnopharmacology

    PubMed Central

    Kumar, Neeraj; Kumar, Rajnish; Kishore, Kamal

    2013-01-01

    The genus Onosma L. (Boraginaceae) includes about 150 species distributed world-wide in which only about 75 plants has been described for its morphology and less than 10 plants for their chemical constituents and clinical potential. The phytochemical reports of this genus revels that it comprise mainly aliphatic ketones, lipids, naphthazarins, alkaloids, phenolic compounds, naphthoquinones, flavones while most important are shikonins and onosmins. The plants are traditionally used as laxative, anthelmintic and for alexipharmic effects. The plants are also equally use in eye, blood diseases, bronchitis, abdominal pain, stangury, thirst, itch, lecoderma, fever, wounds, burns, piles and urinary calculi. The flowers of various plants are prescribed as stimulants, cardiotonic, in body swelling while leaves are used as purgative and in cutaneous eruptions. The roots are used for coloring food stuffs, oils and dying wool and in medicinal preparations. This review emphasizes the distribution, morphology, phytochemical constituents, ethnopharmacology, which may help in future research. PMID:24347922

  14. Preliminary oxidation in histochemical staining methods for cholesterol.

    PubMed

    Adams, C W; High, O B

    1980-08-01

    The need for preliminary oxidation with histochemical methods for cholesterol was investigated on silica-coated sheets and in tissue sections. The techniques used were the Schultz reaction, perchloric acid-naphthoquinone (PAN), Lewis & Lobban's ferric alum-sulphuric acid reagent and Okamoto's iodine-sulphuric acid. The oxidants assessed were ferric chloride, ferric alum, potassium permanganate, ammonium sulphamate and ultraviolet light. The best combinations amongst those tested in order of reactivity were FeCl3-PAN, ferric alum-Schultz, Lewis-Lobban (no additional oxidant), iodine-sulphuric acid (no additional oxidant). Authentic preparations of cholesterol oxidation products were stained with these methods, but the nature of the oxidized product in the preliminary stage could not be determined. PMID:6157826

  15. Juglone induces cell death of Acanthamoeba through increased production of reactive oxygen species.

    PubMed

    Jha, Bijay Kumar; Jung, Hui-Jung; Seo, Incheol; Suh, Seong-Il; Suh, Min-Ho; Baek, Won-Ki

    2015-12-01

    Juglone (5-hydroxy-1,4-naphthoquinone) is a major chemical constituent of Juglans mandshruica Maxim. Recent studies have demonstrated that juglone exhibits anti-cancer, anti-bacterial, anti-viral, and anti-parasitic properties. However, its effect against Acanthamoeba has not been defined yet. The aim of this study was to investigate the effect of juglone on Acanthamoeba. We demonstrate that juglone significantly inhibits the growth of Acanthamoeba castellanii at 3-5 μM concentrations. Juglone increased the production of reactive oxygen species (ROS) and caused cell death of A. castellanii. Inhibition of ROS by antioxidant N-acetyl-l-cysteine (NAC) restored the cell viability. Furthermore, our results show that juglone increased the uptake of mitochondrial specific dye. Collectively, these results indicate that ROS played a significant role in the juglone-induced cell death of Acanthamoeba.

  16. Biodegradation kinetics of naphthalene in nonaqueous phase liquid-water mixed batch systems: Comparison of model predictions and experimental results

    SciTech Connect

    Ghoshal, S.; Luthy, R.G.

    1998-02-05

    A model is formulated to describe dissolution of naphthalene from an insoluble nonaqueous phase liquid (NAPL) and its subsequent biodegradation in the aqueous phase in completely mixed batch reactors. The physicochemical processes of equilibrium partitioning and mass transfer of naphthalene between the NAPL and aqueous phases were incorporated into the model. Biodegradation kinetics were described by Monod`s microbial growth kinetic model, modified to account for the inhibitory effects of 1,2-naphthoquinone formed during naphthalene degradation under certain conditions. System parameters and biokinetic coefficients pertinent to the NAPL-water systems were determined either by direct measurement or from nonlinear regression of the naphthalene mineralization profiles obtained from batch reactor tests with two-component NAPLs comprised of naphthalene and heptamethylnonane. The NAPLs contained substantial mass of naphthalene, and naphthalene biodegradation kinetics were evaluated over the time required for near complete depletion of naphthalene from the NAPL.

  17. One-pot, sequential four-component synthesis of benzo[c]pyrano[3,2-a]phenazine, bis-benzo[c]pyrano[3,2-a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives using 1,4-diazabicyclo[2.2.2]octane (DABCO) as an efficient and reusable solid base catalyst.

    PubMed

    Hasaninejad, Alireza; Firoozi, Somayeh

    2013-08-01

    1,4-Diazabicyclo[2.2.2]octane (DABCO) has been used as an efficient and reusable solid base catalyst for the one-pot, two-step, four-component synthesis of pyrano[3,2-a]phenazine derivatives by the condensation reaction of 2-hydroxy-1,4-naphthoquinone, 1,2-diamines, carbonyl compounds and alkylmalonates under conventional heating as well as microwave irradiation. This procedure has also been applied successfully for the synthesis of novel bis- benzo[c]pyrano[3,2-a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives. Using this procedure, all the products were obtained in good to excellent yields. The catalyst has been recovered and reused several times without any loss of reactivity.

  18. Laser flash photolysis and magnetic-field-effect studies on interaction of thymine and thymidine with menadione: role of sugar in controlling reaction pattern

    NASA Astrophysics Data System (ADS)

    Bose, Adity; Dey, Debarati; Basu, Samita

    2008-04-01

    The magnetic field effect (MFE) in conjunction with laser flash photolysis has been used for the study of the interaction of one of the small drug like quinone molecules, 2-methyl, 1,4-naphthoquinone, commonly known as menadione (MQ), with one of the DNA bases, thymine (THN), and its corresponding nucleoside, thymidine (THDN), in acetonitrile (ACN) and sodium dodecylsulfate (SDS) micelles. It has been observed that THN undergoes electron transfer (ET) and hydrogen (H) abstraction with MQ, while THDN undergoes only H abstraction in both the media. However, our earlier studies showed that a purine base, adenine (ADN), and its nucleoside, 2'-deoxyadenosine (ADS), undergo ET in ACN and H abstraction in SDS. Here we have attempted to explain the differences in the reactions of these DNA bases with MQ. We also reveal the crucial role of a sugar unit in altering the behavior of purine and pyrimidine bases with respect to ET and H abstraction.

  19. [Chemical constituents from the seed coat of Juglans regia].

    PubMed

    Liu, Chuanshui; Tai, Zhigang; Feng, Siquan; Fang, Yunshan; Cai, Le; Ding, Zhongtao

    2012-05-01

    Fifteen compounds were isolated from the seed coat of Juglans regia by silica gel, MCI gel and Sephadex LH-20 gel column chromatography, as well as high preparative performance liquid chromatography. Their structures were identified as salidroside (1), (6S, 9S)-roseoside (2), (6S, 9R)-roseoside (3), blumenol C glucoside (4), byzantionoside B (5), 5-hydroxy-2-methoxy-1, 4-naphthoquinone (6), gallic acid (7), glycerol 1-(9Z-octadecenoate)-2-(9Z, 12Z-octadecadienoate)-3-(9Z, 12Z, 15Z-octadecatrienoate) (8), glycerol 1, 2, 3-tri-(9Z, 12Z-octadecadienoate) (9), glycerol 1, 2, 3-tri-(9Z, 12Z, 15Z-octadecatrienoate) (10), glycerol 1-hexadecanoate-2, 3-di-(9Z, 12Z-octadecadienoate) (11) on the basis of EI-MS, FAB-MS and NMR spectra. Moreover, 35 volatile compounds were identified by GC-MS.

  20. Two new quinones from the roots of Juglans mandshurica.

    PubMed

    Jin, Mei; Sun, Jinfeng; Li, Ren; Diao, Shengbao; Zhang, Changhao; Cui, Jiongmo; Son, Jong-Keun; Zhou, Wei; Li, Gao

    2016-09-01

    Two new quinones, 1-hydroxy-5-pentyl-anthraquinone (1) and 4-(5-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino)-butyric acid methyl ester (2), together with two known quinones, 5-hydroxy-2-(2-hydroxy-ethylamino)-(1,4) naphthoquinone (3) and juglone (4) were isolated from the roots of Juglans mandshurica (Juglandaceae). Their structures were elucidated on the basis of spectral data. Compound 3 was isolated from the Juglans genus for the first time. Compounds 1-4 exhibited significant cytotoxicity towards cultured MDA-MB231, HepG2 and SNU638 cells with IC50 values ranging from 4.46 to 88.47 μM.

  1. Fluorometric identification of 5-methylcytosine modification in DNA: combination of photosensitized oxidation and invasive cleavage.

    PubMed

    Yamada, Hisatsugu; Tanabe, Kazuhito; Nishimoto, Sei-ichi

    2008-01-01

    An efficient fluorometric detection system of DNA methylation has been developed by a combination of a photooxidative DNA cleavage reaction with 2-methyl-1,4-naphthoquinone (NQ) chromophore and an invasive cleavage reaction with human Flap endonuclease-1. Enzymatic treatment of a mixture of photochemically fragmented target oligodeoxynucleotides (ODNs) at 5-methylcytosine mC) and hairpin-like probe oligomer possessing a fluorophore (F) and a quencher (D) resulted in a dramatic enhancement of fluorescence. In contrast, fluorescence emission for the ODN containing cytosine but not mC at the target sequence was extremely weak. In addition, by monitoring the fluorescence change, this system allows for the detection of mC in DNA at subfemtomole amounts. This system would provide a highly sensitive protocol for determining the methylation status in DNA by fluorescence emission.

  2. Total Syntheses of Juglorescein and Juglocombins A and B.

    PubMed

    Kamo, Shogo; Yoshioka, Kai; Kuramochi, Kouji; Tsubaki, Kazunori

    2016-08-22

    Total syntheses of juglorescein and juglocombins A and B are reported. The highly oxygenated 6/6/5/6/6-fused pentacyclic ring system of these natural products was constructed through a bioinspired dimerization of 1,4-naphthoquinone. Notably, five new stereogenic centers were constructed in a single step by the dimerization reaction. The epoxide intermediate obtained from the dimerization was successfully converted into juglocombins A and B through photoinduced reduction of the epoxide, dehydration, and conversion of the resultant quinone into a hydroquinone derivative. The same epoxide intermediate was also converted into a dicarboxylic acid, which was transformed into juglorescein through intramolecular lactonization, hydrolysis of the resulting lactone, and removal of the protecting groups. Furthermore, the relative and absolute configurations of juglorescein and juglocombins A and B were determined. PMID:27460486

  3. Juglone induces cell death of Acanthamoeba through increased production of reactive oxygen species.

    PubMed

    Jha, Bijay Kumar; Jung, Hui-Jung; Seo, Incheol; Suh, Seong-Il; Suh, Min-Ho; Baek, Won-Ki

    2015-12-01

    Juglone (5-hydroxy-1,4-naphthoquinone) is a major chemical constituent of Juglans mandshruica Maxim. Recent studies have demonstrated that juglone exhibits anti-cancer, anti-bacterial, anti-viral, and anti-parasitic properties. However, its effect against Acanthamoeba has not been defined yet. The aim of this study was to investigate the effect of juglone on Acanthamoeba. We demonstrate that juglone significantly inhibits the growth of Acanthamoeba castellanii at 3-5 μM concentrations. Juglone increased the production of reactive oxygen species (ROS) and caused cell death of A. castellanii. Inhibition of ROS by antioxidant N-acetyl-l-cysteine (NAC) restored the cell viability. Furthermore, our results show that juglone increased the uptake of mitochondrial specific dye. Collectively, these results indicate that ROS played a significant role in the juglone-induced cell death of Acanthamoeba. PMID:26358271

  4. Cytotoxic action of juglone and plumbagin: a mechanistic study using HaCaT keratinocytes.

    PubMed

    Inbaraj, J Johnson; Chignell, Colin F

    2004-01-01

    Juglone (5-hydroxy-1,4-naphthoquinone) and plumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone) are yellow pigments found in black walnut (Juglans regia). Herbal preparations derived from black walnut have been used as hair dyes and skin colorants in addition to being applied topically for the treatment of acne, inflammatory diseases, ringworm, and fungal, bacterial, or viral infections. We have studied the cytotoxicity of these quinones to HaCaT keratinocytes. Exposure to juglone or plumbagin (1-20 microM) resulted in a concentration-dependent decrease in cell viability. The cytotoxicity of these quinones is due to two different mechanisms, namely, redox cycling and reaction with glutathione (GSH). Redox cycling results in the generation of the corresponding semiquinone radicals, which were detected by electron paramagnetic resonance. Incubation of keratinocytes with the quinones generated hydrogen peroxide (H(2)O(2)) and resulted in the oxidation of GSH to GSSG. Depletion of GSH by buthionine sulfoximine enhanced semiquinone radical production, increased H(2)O(2) generation, and produced greater cytotoxicity, suggesting that GSH plays an important protective role. Both quinones decreased the intracellular levels of GSH. However, plumbagin stoichiometrically converted GSH to GSSG, indicating that redox cycling is its main metabolic pathway. In contrast, much of the GSH lost during juglone exposure, especially at the higher concentrations (10 and 20 microM), did not appear as GSSG, suggesting that the cytotoxicity of this quinone may also involve nucleophilic addition to GSH. Our findings indicate that topical preparations containing juglone and plumbagin should be used with care as their use may damage the skin. However, it is probable that the antifungal, antiviral, and antibacterial properties of these quinones are the result of redox cycling. PMID:14727919

  5. Time-resolved visible and infrared difference spectroscopy for the study of photosystem I with different quinones incorporated into the A1 binding site.

    PubMed

    Makita, Hiroki; Zhao, Nan; Hastings, Gary

    2015-03-01

    Room (298 K) and low (77K) temperature time-resolved visible and infrared difference spectroscopy has been used to study photosystem I particles with phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone), menadione (2-methyl-1,4-naphthoquinone) and plastoquinone 9 (2,3-dimethyl-5-prenyl-l,4-benzoquinone), incorporated into the A1 binding site. Concentrated samples in short path-length (~5 μm) sample cells are typically used in FTIR experiments. Measurements were undertaken using standard "dilute" samples at 298 K, and concentrated (~5×) samples at both 298 and 77K. No concentration induced alterations in the flash-induced absorption changes were observed. Concentrated samples in short path-length cells form a transparent film at 77K, and could therefore be studied spectroscopically at 77K without addition of a cryoprotectant. At 298 K, for photosystem I with plastoquinone 9/menadione/phylloquinone incorporated, P700+FA/B- radical pair recombination is characterized by a time constant of 3/14/80 ms, and forward electron transfer from A1A- to Fx by a time constant of 211/3.1/0.309 μs, respectively. At 77K, for concentrated photosystem I with menadione/phylloquinone incorporated, P700+A1- radical pair recombination is characterized by a time constant of 240/340 μs, with this process occurring in 58/39% of the PSI particles, respectively. The origin of these differences is discussed. Marcus electron transfer theory in combination with kinetic modeling is used to simulate the observed electron transfer time constants at 298 K. This simulation allows an estimate of the redox potential for the different quinones in the A1 binding site.

  6. Design, Synthesis, Biological Evaluation, and Antioxidant and Cytotoxic Activity of Heteroatom-Substituted 1,4-Naphtho- and Benzoquinones.

    PubMed

    Deniz, Nahide Gülşah; Ibis, Cemil; Gokmen, Zeliha; Stasevych, Maryna; Novikov, Volodymyr; Komarovska-Porokhnyavets, Olena; Ozyurek, Mustafa; Guclu, Kubilay; Karakas, Didem; Ulukaya, Engin

    2015-01-01

    In the present paper, we report the synthesis, characterization, and biological evaluation as antifungal, antibacterial, antioxidant, and cytotoxic/anticancer agents of N-, S-, O-substituted-1,4-naphtho- and 2,5-bis(amino-substituted)-1,4-benzoquinone derivatives. In the synthesized compounds, antimicrobial activity at low concentrations against Escherichia coli B-906, Staphylococcus aureus 209-P, and Mycobacterium luteum B-917 bacteria and Candida tenuis VKM Y-70 and Aspergillus niger F-1119 fungi in comparison with controls was identified. 2-(N-Diphenylmethylpiperazin-1-yl)-3-chloro-1,4-naphthoquinone 9a was the most potent, with a minimum inhibitory concentration value of 3.9 µg/mL against test culture M. luteum. The synthesized compounds were screened for their antioxidant capacity using the cupric-reducing antioxidant capacity (CUPRAC) method. 2,2'-[1-(2-Aminoethyl)piperazin-1-yl]-3,3'-dichloro-bis(1,4-naphthoquinone) 10 showed the highest antioxidant capacity, with a 0.455 CUPRAC-trolox equivalent antioxidant capacity (TEAC) coefficient. Other parameters of antioxidant activity (scavenging effects on OH(·), O2(·-), and H2O2) of these compounds were also determined. The cytotoxic activity of the compounds was investigated by employing the sulforhodamine B cell viability assay against A549 (lung), MCF-7 (breast), DU145 (prostate), and HT-29 (colon) cancer cell lines. Compound 10 exhibited the most powerful cytotoxic activity at a concentration of 20 µM against all cell lines. In addition to the strongest antioxidant activity of compound 10, it also had lowest IC50 values (<3 µM), warranting further in vivo studies due to its anticancer activity. PMID:26633024

  7. Evaluation of the inhibition potential of plumbagin against cytochrome P450 using LC-MS/MS and cocktail approach

    PubMed Central

    Chen, Ang; Zhou, Xiaojing; Tang, Shuowen; Liu, Mingyao; Wang, Xin

    2016-01-01

    Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), a natural naphthoquinone compound isolated from roots of Plumbago zeylanica L., has drawn a lot of attention for its plenty of pharmacological properties including antidiabetes and anti-cancer. The aim of this study was to investigate the effects of plumbagin on CYP1A2, CYP2B1/6, CYP2C9/11, CYP2D1/6, CYP2E1 and CYP3A2/4 activities in human and rat liver and evaluate the potential herb-drug interactions using the cocktail approach. All CYP substrates and their metabolites were analyzed using high-performance liquid chromatography–tandem mass spectrometry (LC-MS/MS). Plumbagin presented non-time-dependent inhibition of CYP activities in both human and rat liver. In humans, plumbagin was not only a mixed inhibitor of CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, but also a non-competitive inhibitor of CYP1A2, with Ki values no more than 2.16 μM. In rats, the mixed inhibition of CYP1A2 and CYP2D1, and competitive inhibition for CYP2B1, CYP2C11 and CYP2E1 with Ki values less than 9.93 μM were observed. In general, the relatively low Ki values of plumbagin in humans would have a high potential to cause the toxicity and drug interactions involving CYP enzymes. PMID:27329697

  8. Anti-Tumor Effects of Novel 5-O-Acyl Plumbagins Based on the Inhibition of Mammalian DNA Replicative Polymerase Activity

    PubMed Central

    Kawamura, Moe; Kuriyama, Isoko; Maruo, Sayako; Kuramochi, Kouji; Tsubaki, Kazunori; Yoshida, Hiromi; Mizushina, Yoshiyuki

    2014-01-01

    We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins enhanced mammalian pol inhibition and their cytotoxic activity. Plumbagin conjugated with chains consisting of more than C18-unsaturated fatty acids strongly inhibited the activities of calf pol α and human pol γ. Plumbagin conjugated with oleic acid (C18:1-acyl plumbagin) showed the strongest suppression of human colon carcinoma (HCT116) cell proliferation among the ten synthesized 5-O-acyl plumbagins. The inhibitory activity on pol α, a DNA replicative pol, by these compounds showed high correlation with their cancer cell proliferation suppressive activity. C18:1-Acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. This compound inhibited the proliferation of various human cancer cell lines, and was the cytotoxic inhibitor showing strongest inhibition towards HT-29 colon cancer cells (LD50 = 2.9 µM) among the nine cell lines tested. In an in vivo anti-tumor assay conducted on nude mice bearing solid tumors of HT-29 cells, C18:1-acyl plumbagin was shown to be a promising tumor suppressor. These data indicate that novel 5-O-acyl plumbagins act as anti-cancer agents based on mammalian DNA replicative pol α inhibition. Moreover, the results suggest that acylation of plumbagin is an effective chemical modification to improve the anti-cancer activity of vitamin K3 derivatives, such as plumbagin. PMID:24520419

  9. Design, Synthesis, Biological Evaluation, and Antioxidant and Cytotoxic Activity of Heteroatom-Substituted 1,4-Naphtho- and Benzoquinones.

    PubMed

    Deniz, Nahide Gülşah; Ibis, Cemil; Gokmen, Zeliha; Stasevych, Maryna; Novikov, Volodymyr; Komarovska-Porokhnyavets, Olena; Ozyurek, Mustafa; Guclu, Kubilay; Karakas, Didem; Ulukaya, Engin

    2015-01-01

    In the present paper, we report the synthesis, characterization, and biological evaluation as antifungal, antibacterial, antioxidant, and cytotoxic/anticancer agents of N-, S-, O-substituted-1,4-naphtho- and 2,5-bis(amino-substituted)-1,4-benzoquinone derivatives. In the synthesized compounds, antimicrobial activity at low concentrations against Escherichia coli B-906, Staphylococcus aureus 209-P, and Mycobacterium luteum B-917 bacteria and Candida tenuis VKM Y-70 and Aspergillus niger F-1119 fungi in comparison with controls was identified. 2-(N-Diphenylmethylpiperazin-1-yl)-3-chloro-1,4-naphthoquinone 9a was the most potent, with a minimum inhibitory concentration value of 3.9 µg/mL against test culture M. luteum. The synthesized compounds were screened for their antioxidant capacity using the cupric-reducing antioxidant capacity (CUPRAC) method. 2,2'-[1-(2-Aminoethyl)piperazin-1-yl]-3,3'-dichloro-bis(1,4-naphthoquinone) 10 showed the highest antioxidant capacity, with a 0.455 CUPRAC-trolox equivalent antioxidant capacity (TEAC) coefficient. Other parameters of antioxidant activity (scavenging effects on OH(·), O2(·-), and H2O2) of these compounds were also determined. The cytotoxic activity of the compounds was investigated by employing the sulforhodamine B cell viability assay against A549 (lung), MCF-7 (breast), DU145 (prostate), and HT-29 (colon) cancer cell lines. Compound 10 exhibited the most powerful cytotoxic activity at a concentration of 20 µM against all cell lines. In addition to the strongest antioxidant activity of compound 10, it also had lowest IC50 values (<3 µM), warranting further in vivo studies due to its anticancer activity.

  10. Glanduliferins A and B, two new glucosylated steroids from Impatiens glandulifera, with in vitro growth inhibitory activity in human cancer cells.

    PubMed

    Cimmino, Alessio; Mathieu, Véronique; Evidente, Marco; Ferderin, Marlène; Moreno Y Banuls, Laetitia; Masi, Marco; De Carvalho, Annelise; Kiss, Robert; Evidente, Antonio

    2016-03-01

    Impatiens glandulifera has been imported from Himalaya in Europe and is considered as an invasive alien plant whose spreading arouses increasing interest among scientific literature. Via anti-cancer bioguiding, two new glucosylated steroids, named glanduliferins A and B, were isolated from the dried stem of I. glandulifera plants, together with the well-known α-spinasterol and 2-methoxy-1,4-naphthoquinone, which are also isolated from roots and leaves. They were characterized as 17-(2-hydroxy-2-pentamethylcyclopropyl-ethyl)-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopents[a]phenathren-3-O-(4-O-acetyl)-α-D-glucopyranoside and 17-(4-ethyl-1,5-dimethyl-hex-2-enyl)-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopents[a]phenathren-3-O-(6-O-acetyl)-β-D-glucopyranoside using various NMR and HRESIMS techniques and chemical methods. In vitro determination of the growth inhibitory activity of the four isolated compounds using the MTT colorimetric assay revealed mean IC50 growth inhibitory value of ~30 μM for glanduliferin A while glanduliferin B and α-spinasterol were poorly active till 100 μM. 2-methoxy-1,4-naphthoquinone revealed to be active in the single micromolar digit range as previously described. Quantitative videomicroscopy analyses of the effects of glanduliferins A and B suggested cytostatic rather than cytotoxic activity in U373 glioblastoma (GBM) cells.

  11. Profiling the NIH Small Molecule Repository for Compounds That Generate H2O2 by Redox Cycling in Reducing Environments

    PubMed Central

    2010-01-01

    We have screened the Library of Pharmacologically Active Compounds (LOPAC) and the National Institutes of Health (NIH) Small Molecule Repository (SMR) libraries in a horseradish peroxidase–phenol red (HRP-PR) H2O2 detection assay to identify redox cycling compounds (RCCs) capable of generating H2O2 in buffers containing dithiothreitol (DTT). Two RCCs were identified in the LOPAC set, the ortho-naphthoquinone β-lapachone and the para-naphthoquinone NSC 95397. Thirty-seven (0.02%) concentration-dependent RCCs were identified from 195,826 compounds in the NIH SMR library; 3 singleton structures, 9 ortho-quinones, 2 para-quinones, 4 pyrimidotriazinediones, 15 arylsulfonamides, 2 nitrothiophene-2-carboxylates, and 2 tolyl hydrazides. Sixty percent of the ortho-quinones and 80% of the pyrimidotriazinediones in the library were confirmed as RCCs. In contrast, only 3.9% of the para-quinones were confirmed as RCCs. Fifteen of the 251 arylsulfonamides in the library were confirmed as RCCs, and since we screened 17,868 compounds with a sulfonamide functional group we conclude that the redox cycling activity of the arylsulfonamide RCCs is due to peripheral reactive enone, aromatic, or heterocyclic functions. Cross-target queries of the University of Pittsburgh Drug Discovery Institute (UPDDI) and PubChem databases revealed that the RCCs exhibited promiscuous bioactivity profiles and have populated both screening databases with significantly higher numbers of active flags than non-RCCs. RCCs were promiscuously active against protein targets known to be susceptible to oxidation, but were also active in cell growth inhibition assays, and against other targets thought to be insensitive to oxidation. Profiling compound libraries or the hits from screening campaigns in the HRP-PR H2O2 detection assay significantly reduce the timelines and resources required to identify and eliminate promiscuous nuisance RCCs from the candidates for lead optimization. PMID:20070233

  12. Effect of Simultaneous Administration of Dihydroxyacetone on the Diffusion of Lawsone Through Various In Vitro Skin Models.

    PubMed

    Munt, Daniel J; Grana, Anne; Hulce, Martin; Fusaro, Ramon M; Dash, Alekha K

    2015-12-01

    Unprotected sunlight exposure is a risk factor for a variety of cutaneous cancers. Topically used dihydroxyacetone (DHA) creates, via Maillard reaction, chemically fixed keratin sunscreen in the stratum corneum with significant protection against UVA/Soret radiation. When used in conjunction with naphthoquinones a naphthoquinone-modified DHA Maillard reaction is produced that provides protection across the UVB/UVA/Soret spectra lasting up to 1 week, resisting sweating and contact removal. The aim of this study was to examine a simplified version of this formulation for effect on UV transmission and to determine if penetration levels merit toxicity concerns. Permeability was demonstrated for freshly prepared DHA (30 mg/mL) and lawsone (0.035 mg/mL) alone and in combination using a side-by-side diffusion apparatus at 37°C over 48 h across shed snake skin and dermatomed pig skin. These samples were then examined for effectiveness and safety. Concentrations were determined by HPLC and UPLC monitored from 250-500 nm. Lawsone flux significantly decreased across pig skin (20.8 (± 4.8) and 0.09 (± 0.1) mg/cm(2) h without and with DHA, respectively) but did not change across shed snake skin in the presence of DHA. Significantly reduced lawsone concentration was noted in donor chambers of combined solutions. Damage was not observed in any skins. Darker coloration with greater UV absorbance was observed in skins exposed to the combined solution versus individual solutions. This study confirmed that combined DHA and lawsone provided effective blocking of ultraviolet light through products bound in keratinized tissue. DHA permeation levels in pig skin suggest further in vitro and in vivo study is required to determine the safety of this system.

  13. Cytotoxicity of naphthalene toward cells from target and non-target organs in vitro.

    PubMed

    Kedderis, Gregory L; Shepard, Kim G; Recio, Leslie

    2014-02-25

    Chronic inhalation exposure to high concentrations of naphthalene produced nasal tumors in rats and lung tumors in female mice. Naphthalene bioactivation is required for target organ toxicity and cytotoxicity in target organs may be involved in tumor development. The present studies characterized the dose-response relationships for naphthalene-induced glutathione (GSH) depletion, effects on cellular ATP, and cytotoxicity in cells from both target (lung, nasal epithelium) and non-target (liver) organs in vitro using cells from F-344 rats, B6C3F1 mice and humans. The cells were incubated with various concentrations of naphthalene in sealed glass flasks for 3h, then placed in monolayer culture in fresh media for 24h to examine the repair or progression of damage. Naphthalene was a low potency cytotoxicant in vitro, with 500 μM frequently observed as a no-observed adverse effect concentration or lowest observed adverse effect concentration. Naphthalene exposure produced dose-dependent decreases in cellular GSH, ATP and viability in rat, mouse and human hepatocytes at concentrations >500 μM. Human nasal respiratory epithelial cells exhibited greater naphthalene cytotoxicity than rat or mouse nasal respiratory epithelial cell preparations. Rat nasal respiratory epithelial cell preparations metabolized naphthalene through pathways leading to the preferential formation of 1,2-naphthoquinone GSH conjugates rather than 1,4-naphthoquinone GSH conjugates observed in rat hepatocytes or mouse nasal respiratory epithelial cells, consistent with the suggestion that this bioactivation pathway may be involved in rat nasal tumor development. Naphthalene exposures of ≥500 μM decreased cellular GSH and ATP in rat, mouse and human lung cell preparations. The variability of the responses of the human lung cell preparations was consistent with the known variability of CYP activities in human lung tissue. The results of these studies can be used as the basis for future studies of the

  14. Cytotoxic Compounds from Juglans sinensis Dode Display Anti-Proliferative Activity by Inducing Apoptosis in Human Cancer Cells.

    PubMed

    Lee, Yoo Jin; Cui, Jun; Lee, Jun; Han, Ah-Reum; Lee, Eun Byul; Jang, Ho Hee; Seo, Eun Kyoung

    2016-01-01

    Phytochemical investigation of the bark of Juglans sinensis Dode (Juglandaceae) led to the isolation of two active compounds, 8-hydroxy-2-methoxy-1,4-naphthoquinone (1) and 5-hydroxy-2-methoxy-1,4-naphthoquinone (2), together with 15 known compounds 3-17. All compounds were isolated from this plant for the first time. The structures of 1 and 2 were elucidated by spectroscopic data analysis, including 1D and 2D NMR experiments. Compounds 1-17 were tested for their cytotoxicity against the A549 human lung cancer cell line; compounds 1 and 2 exhibited significant cytotoxicity and additionally had potent cytotoxicity against six human cancer cell lines, MCF7 (breast cancer), SNU423 (liver cancer), SH-SY5Y (neuroblastoma), HeLa (cervical cancer), HCT116 (colorectal cancer), and A549 (lung cancer). In particular, breast, colon, and lung cancer cells were more sensitive to the treatment using compound 1. In addition, compounds 1 and 2 showed strong cytotoxic activity towards human breast cancer cells MCF7, HS578T, and T47D, but not towards MCF10A normal-like breast cells. They also inhibited the colony formation of MCF7, A549, and HCT116 cells in a dose-dependent manner. Flow cytometry analysis revealed that the percentage of apoptotic cells significantly increased in MCF7 cells upon the treatment with compounds 1 and 2. The mechanism of cell death caused by compounds 1 and 2 may be attributed to the upregulation of Bax and downregulation of Bcl2. These findings suggest that compounds 1 and 2 may be regarded as potential therapeutic agents against cancer.

  15. Glanduliferins A and B, two new glucosylated steroids from Impatiens glandulifera, with in vitro growth inhibitory activity in human cancer cells.

    PubMed

    Cimmino, Alessio; Mathieu, Véronique; Evidente, Marco; Ferderin, Marlène; Moreno Y Banuls, Laetitia; Masi, Marco; De Carvalho, Annelise; Kiss, Robert; Evidente, Antonio

    2016-03-01

    Impatiens glandulifera has been imported from Himalaya in Europe and is considered as an invasive alien plant whose spreading arouses increasing interest among scientific literature. Via anti-cancer bioguiding, two new glucosylated steroids, named glanduliferins A and B, were isolated from the dried stem of I. glandulifera plants, together with the well-known α-spinasterol and 2-methoxy-1,4-naphthoquinone, which are also isolated from roots and leaves. They were characterized as 17-(2-hydroxy-2-pentamethylcyclopropyl-ethyl)-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopents[a]phenathren-3-O-(4-O-acetyl)-α-D-glucopyranoside and 17-(4-ethyl-1,5-dimethyl-hex-2-enyl)-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopents[a]phenathren-3-O-(6-O-acetyl)-β-D-glucopyranoside using various NMR and HRESIMS techniques and chemical methods. In vitro determination of the growth inhibitory activity of the four isolated compounds using the MTT colorimetric assay revealed mean IC50 growth inhibitory value of ~30 μM for glanduliferin A while glanduliferin B and α-spinasterol were poorly active till 100 μM. 2-methoxy-1,4-naphthoquinone revealed to be active in the single micromolar digit range as previously described. Quantitative videomicroscopy analyses of the effects of glanduliferins A and B suggested cytostatic rather than cytotoxic activity in U373 glioblastoma (GBM) cells. PMID:26732071

  16. Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells

    PubMed Central

    Pan, Shu-Ting; Qin, Yiru; Zhou, Zhi-Wei; He, Zhi-Xu; Zhang, Xueji; Yang, Tianxin; Yang, Yin-Xue; Wang, Dong; Zhou, Shu-Feng; Qiu, Jia-Xuan

    2015-01-01

    Tongue squamous cell carcinoma (TSCC) is the most common malignancy in oral and maxillofacial tumors with highly metastatic characteristics. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone; PLB), a natural naphthoquinone derived from the roots of Plumbaginaceae plants, exhibits various bioactivities, including anticancer effects. However, the potential molecular targets and underlying mechanisms of PLB in the treatment of TSCC remain elusive. This study employed stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic approach to investigate the molecular interactome of PLB in human TSCC cell line SCC25 and elucidate the molecular mechanisms. The proteomic data indicated that PLB inhibited cell proliferation, activated death receptor-mediated apoptotic pathway, remodeled epithelial adherens junctions pathway, and manipulated nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response signaling pathway in SCC25 cells with the involvement of a number of key functional proteins. Furthermore, we verified these protein targets using Western blotting assay. The verification results showed that PLB markedly induced cell cycle arrest at G2/M phase and extrinsic apoptosis, and inhibited epithelial to mesenchymal transition (EMT) and stemness in SCC25 cells. Of note, N-acetyl-l-cysteine (NAC) and l-glutathione (GSH) abolished the effects of PLB on cell cycle arrest, apoptosis induction, EMT inhibition, and stemness attenuation in SCC25 cells. Importantly, PLB suppressed the translocation of Nrf2 from cytosol to nucleus, resulting in an inhibition in the expression of downstream targets. Taken together, these results suggest that PLB may act as a promising anticancer compound via inhibiting Nrf2-mediated oxidative stress signaling pathway in SCC25 cells. This study provides a clue to fully identify the molecular targets and decipher the underlying mechanisms of PLB in the treatment of TSCC. PMID:26491260

  17. (+/-)-catechin: chemical weapon, antioxidant, or stress regulator?

    PubMed

    Chobot, Vladimir; Huber, Christoph; Trettenhahn, Guenter; Hadacek, Franz

    2009-08-01

    (+/-)-Catechin is a flavan-3-ol that occurs in the organs of many plant species, especially fruits. Health-beneficial effects have been studied extensively, and notable toxic effects have not been found. In contrast, (+/-)-catechin has been implicated as a 'chemical weapon' that is exuded by the roots of Centaurea stoebe, an invasive knapweed of northern America. Recently, this hypothesis has been rejected based on (+/-)-catechin's low phytotoxicity, instability at pH levels higher than 5, and poor recovery from soil. In the current study, (+/-)-catechin did not inhibit the development of white and black mustard to an extent that was comparable to the highly phytotoxic juglone, a naphthoquinone that is allegedly responsible for the allelopathy of the walnut tree. At high stress levels, caused by sub-lethal methanol concentrations in the medium, and a 12 h photoperiod, (+/-)-catechin even attenuated growth retardation. A similar effect was observed when (+/-)-catechin was assayed for brine shrimp mortality. Higher concentrations reduced the mortality caused by toxic concentrations of methanol. Further, when (+/-)-catechin was tested in variants of the deoxyribose degradation assay, it was an efficient scavenger of reactive oxygen species (ROS) when they were present in higher concentrations. This antioxidant effect was enhanced when iron was chelated directly by (+/-)-catechin. Conversely, if iron was chelated to EDTA, pro-oxidative effects were demonstrated at higher concentrations; in this case (+/-)-catechin reduced molecular oxygen and iron to reagents required by the Fenton reaction to produce hydroxyl radicals. A comparison of cyclic voltammograms of (+/-)-catechin with the phytotoxic naphthoquinone juglone indicated similar redox-cycling properties for both compounds although juglone required lower electrochemical potentials to enter redox reactions. In buffer solutions, (+/-)-catechin remained stable at pH 3.6 (vacuole) and decomposed at pH 7.4 (cytoplasm

  18. Fractionating ambient humic-like substances (HULIS) for their reactive oxygen species activity - Assessing the importance of quinones and atmospheric aging

    NASA Astrophysics Data System (ADS)

    Verma, Vishal; Wang, Ying; El-Afifi, Rawan; Fang, Ting; Rowland, Janessa; Russell, Armistead G.; Weber, Rodney J.

    2015-11-01

    In this paper, we present a technique to identify the redox-active components of fine organic aerosols by fractionating humic-like substances (HULIS). We applied this technique to a dithiothreitol (DTT) assay - a measure of the capability of PM to generate reactive oxygen species (ROS), and assessed the contribution of quinones to the DTT activity of ambient water-soluble PM. Filter samples from the Southeastern Center for Air Pollution & Epidemiology (SCAPE) were extracted in water and then passed-through a C-18 column to isolate the HULIS fraction by retention on the column. The HULIS was then eluted with a sequence of solvents of increasing polarity, i.e., hexane, dichloromethane (DCM) and then methanol. Each of these eluted fractions was analyzed for DTT activity. The methanol fraction was found to possess most of the DTT activity (>70%), while the hexane fraction had the least activity (<5%), suggesting that the ROS-active compounds of ambient water-soluble PM2.5 HULIS are mostly polar in nature. A number of quinones thought to contribute to ambient PM DTT activity were also tested. 1,4 Naphthoquinone (1,4 NQ), 1,2 Naphthoquinone (1,2 NQ), 9,10 Phenanthrenequinone (PQ), and 5-hydroxy-1,4 NQ were analyzed by the same protocol. The hexane fraction of two quinones (PQ, and 1,4 NQ) was the most-DTT active, while methanol was the least, confirming that PQ, 1,4 NQ, and 1,2 NQ (which could not be recovered from the column) do not contribute significantly to the water-soluble DTT activity of ambient PM2.5. However, an oxygenated derivative of 1,4 NQ, (5-hydroxy-1,4 NQ), which is also intrinsically more DTT-active than 1,4 NQ, was mostly (>60%) eluted in methanol. The results demonstrate the importance of atmospheric aging (oxidation) of organic aerosols in enhancing the ROS activity of ambient PM.

  19. Plumbagin induces G2/M arrest, apoptosis, and autophagy via p38 MAPK- and PI3K/Akt/mTOR-mediated pathways in human tongue squamous cell carcinoma cells

    PubMed Central

    Pan, Shu-Ting; Qin, Yiru; Zhou, Zhi-Wei; He, Zhi-Xu; Zhang, Xueji; Yang, Tianxin; Yang, Yin-Xue; Wang, Dong; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2015-01-01

    Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone; PLB), a naturally occurring naphthoquinone isolated from the roots of Plumbaginaceae plants, has been reported to possess anticancer activities in both in vitro and in vivo studies, but the effect of PLB on tongue squamous cell carcinoma (TSCC) is not fully understood. This study aimed to investigate the effects of PLB on cell cycle distribution, apoptosis, and autophagy, and the underlying mechanisms in the human TSCC cell line SCC25. The results have revealed that PLB exerted potent inducing effects on cell cycle arrest, apoptosis, and autophagy in SCC25 cells. PLB arrested SCC25 cells at the G2/M phase in a concentration- and time-dependent manner with a decrease in the expression level of cell division cycle protein 2 homolog (Cdc2) and cyclin B1 and increase in the expression level of p21 Waf1/Cip1, p27 Kip1, and p53 in SCC25 cells. PLB markedly induced apoptosis and autophagy in SCC25 cells. PLB decreased the expression of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) while increasing the expression level of the pro-apoptotic protein Bcl-2-associated X protein (Bax) in SCC25 cells. Furthermore, PLB inhibited phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β), and p38 mitogen-activated protein kinase (p38 MAPK) pathways as indicated by the alteration in the ratio of phosphorylation level over total protein expression level, contributing to the autophagy inducing effect. In addition, we found that wortmannin (a PI3K inhibitor) and SB202190 (a selective inhibitor of p38 MAPK) strikingly enhanced PLB-induced autophagy in SCC25 cells, suggesting the involvement of PI3K- and p38 MAPK-mediated signaling pathways. Moreover, PLB induced intracellular reactive oxygen species (ROS) generation and this effect was attenuated by l-glutathione (GSH) and n-acetyl-l-cysteine (NAC). Taken

  20. Microbial fuel cell using anaerobic respiration as an anodic reaction and biomineralized manganese as a cathodic reactant.

    PubMed

    Rhoads, Allison; Beyenal, Haluk; Lewandowski, Zbigniew

    2005-06-15

    We have operated a microbial fuel cell in which glucose was oxidized by Klebsiella pneumoniae in the anodic compartment, and biomineralized manganese oxides, deposited by Leptothrix discophora, were electrochemically reduced in the cathodic compartment. In the anodic compartment, to facilitate the electron transfer from glucose to the graphite electrode, we added a redox mediator, 2-hydroxy-1,4-naphthoquinone. We did not add any redox mediator to the cathodic compartment because the biomineralized manganese oxides were deposited on the surface of a graphite electrode and were reduced directly by electrons from the electrode. We have demonstrated that biomineralized manganese oxides are superiorto oxygen when used as cathodic reactants in microbial fuel cells. The current density delivered by using biomineralized manganese oxides as the cathodic reactant was almost 2 orders of magnitude higher than that delivered using oxygen. Several fuel cells were operated for 500 h, reaching anodic potentials of -441.5 +/- 31 mVscE and cathodic potentials of +384.5 +/- 64 mVscE. When the electrodes were connected by a 50 Ohms resistor, the fuel cell delivered the peak power density of 126.7 +/- 31.5 mW/m2.

  1. Determination of histamine in wines with an on-line pre-column flow derivatization system coupled to high performance liquid chromatography.

    PubMed

    García-Villar, Natividad; Saurina, Javier; Hernández-Cassou, Santiago

    2005-09-01

    A new rapid and sensitive high performance liquid chromatography (HPLC) method for determining histamine in red wine samples, based on continuous flow derivatization with 1,2-naphthoquinone-4-sulfonate (NQS), is proposed. In this system, samples are derivatized on-line in a three-channel flow manifold for reagent, buffer and sample. The reaction takes place in a PTFE coil heated at 80 degrees C and with a residence time of 2.9 min. The reaction mixture is injected directly into the chromatographic system, where the histamine derivative is separated from other aminated compounds present in the wine matrix in less than ten minutes. The HPLC procedure involves a C18 column, a binary gradient of 2% acetic acid-methanol as a mobile phase, and UV detection at 305 nm. Analytical parameters of the method are evaluated using red wine samples. The linear range is up to 66.7 mg L(-1) (r = 0.9999), the precision (RSD) is 3%, the detection limit is 0.22 mg L(-1), and the average histamine recovery is 101.5% +/- 6.7%. Commercial red wines from different Spanish regions are analyzed with the proposed method.

  2. Determination of biogenic amines in wines by pre-column derivatization and high-performance liquid chromatography coupled to mass spectrometry.

    PubMed

    García-Villar, Natividad; Hernández-Cassou, Santiago; Saurina, Javier

    2009-09-01

    A new HPLC method for determining biogenic amines in wines is developed. This method is based on pre-column amine derivatization, further separation of derivatives and on-line hyphenation of HPLC to atmospheric pressure chemical ionization mass spectrometry (APCI-MS). Biogenic amines have been derivatized with 1,2-naphthoquinone-4-sulfonate at 65 degrees C and pH 9.2 for 5 min. The separation of derivatives has been accomplished in a C(18) analytical column using an elution gradient based on increasing the percentage of methanol. Derivatives have been ionized in positive mode and detected by selected ion monitoring. The operating conditions of the APCI-MS system (voltages, temperatures and gases) have been thoroughly optimized to obtain the maximum sensitivity for all analytes. In the selected conditions, APCI-MS spectra display little fragmentation and good signal-to-noise ratio. Depending on the amine characteristics, the main spectral peaks are due to mono- and di-derivative products. Figures of merit of the method have been established under the selected conditions using red wine samples. Recoveries ranging from 94% to 106% have been obtained which prove excellent accuracy of the method in the determination of histamine, putrescine, cadaverine, tryptamine, phenylethylamine, tyramine and serotonin in red wines. The proposed method has been applied to the analysis of commercial wines from different Spanish regions.

  3. The redox systems of Plasmodium falciparum and Plasmodium vivax: comparison, in silico analyses and inhibitor studies.

    PubMed

    Mohring, F; Pretzel, J; Jortzik, E; Becker, K

    2014-01-01

    Plasmodium falciparum is responsible for the most severe form of human malaria. P. vivax, in contrast, is the most widespread malaria parasite with an enormous impact on health and economy, since the infection is characterized by high rates of relapses. Due to the mild course of malaria tertiana and complicated in vitro culturing conditions of P. vivax, most of the research on malaria parasites has focused on P. falciparum so far. The redox metabolism of P. falciparum is a promising target for novel antimalarial drugs, since maintaining a redox equilibrium is of fundamental importance for the parasite. P. falciparum contains a cytosolic glutathione and thioredoxin system, as well as redox systems in the apicoplast and the mitochondrion. In contrast to P. falciparum, little is known about the redox processes in P. vivax so far. This review summarizes the current knowledge of the redox metabolism in malaria parasites and provides a detailed in silico comparison of the known and mostly well characterized redox enzymes from P. falciparum and the largely unknown redox proteins from P. vivax. Known antimalarials at least partially mediating their antiparasitic activity by influencing the redox balance of Plasmodium, including dehydroepiandrosterone, Mannich bases, methylene blue, and naphthoquinones, are discussed. Furthermore, we present novel inhibitors identified via screening of a compound library from the Leibniz Institute for Natural Product Research and Infection Biology, Jena that are active against the redox-related enzymes thioredoxin reductase, glutathione reductase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase 6- phosphoglucono- lactonase from P. falciparum.

  4. Nematicidal effect of plumbagin on Caenorhabditis elegans: a model for testing a nematicidal drug.

    PubMed

    Chaweeborisuit, Phantip; Suriyonplengsaeng, Chinnawut; Suphamungmee, Worawit; Sobhon, Prasert; Meemon, Krai

    2016-01-01

    Plumbagin, (5-hydroxy-2-methyl-1,4-naphthoquinone), a natural substance found in the roots of plant species in the genus Plumbago, has been used as a traditional medicine against many diseases. In this study, Caenorhabditis elegans was used as a model for testing the anthelmintic effect of plumbagin. The compound exhibited a nematicidal effect against all stages of C. elegans: L4 was least susceptible, while L1 was most susceptible to plumbagin with an LC(50) of 220 and 156 μM, respectively. Plumbagin inhibited C. elegans development from L1 to adult stages with an IC(50) of 235 μM, and body length was also reduced at concentrations of 25 and 50 μg/ml. Brood sizes decreased from 203±6 to 43±6 and 18±3 eggs per hatch in plumbagin-treated worms at 10, 25, 50 μg/ml, respectively. Furthermore, plumbagin was lethal to strains resistant to the nematicides levamisole, albendazole, and ivermectin, indicating that it possesses a strong and unique nematicidal action. Plumbagin decreased the number of mitochondria in hypodermal and intestinal cells and body wall muscles and damaged the ultrastructure of these tissues. Taken together, plumbagin may be a new drug against parasitic nematodes. PMID:27140303

  5. Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-β aggregation and to exert anticholinesterase and antioxidant effects.

    PubMed

    Nepovimova, Eugenie; Uliassi, Elisa; Korabecny, Jan; Peña-Altamira, Luis Emiliano; Samez, Sarah; Pesaresi, Alessandro; Garcia, Gregory E; Bartolini, Manuela; Andrisano, Vincenza; Bergamini, Christian; Fato, Romana; Lamba, Doriano; Roberti, Marinella; Kuca, Kamil; Monti, Barbara; Bolognesi, Maria Laura

    2014-10-23

    We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-β (Aβ) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Aβ. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit. PMID:25259726

  6. Chlorine dioxide-facilitated oxidation of the azo dye amaranth.

    PubMed

    Nadupalli, S; Koorbanally, N; Jonnalagadda, S B

    2011-10-27

    The oxidation reaction of amaranth (trisodium 2-hydroxy-1-(4-sulfonato-1-naphthylazo)naphthalene-3,6-disulfonate or AM(-)) by chlorine dioxide (ClO(2)) in aqueous conditions was investigated in detail. The major reaction products immediately after decolorization of AM(-) were 1,2-naphthoquinone disulfonate sodium salt and 1,4-napthalenedione. The reaction had first-order dependence on both AM(-) and ClO(2). The rate-limiting step involved the reaction between AM(-) and OH(-) ions. The role of hydroxide ion as a catalyst was established. The second-order rate constant increased with pH, from (19.8 ± 0.9) M(-1) s(-1) at pH 7.0, (97.1 ± 2.3) M(-1) s(-1) at pH 8.0 to (132.5 ± 2.8) M(-1) s(-1) at pH 9.0. In the pH range of 6.0-7.5, the catalytic constant for OH(-) ion was 4.0 × 10(9) M(-2) s(-1). The energy and entropy of activation values for the reaction were 50.0 kJ mol(-1) and -658.7 J K(-1) mol(-1), respectively. A probable reaction mechanism was elucidated and was validated by simulations.

  7. Sub-toxic concentrations of volatile organic compounds inhibit extracellular respiration of Escherichia coli cells grown in anodic bioelectrochemical systems.

    PubMed

    Santoro, Carlo; Mohidin, Abeed Fatima; Grasso, Letizia Lo; Seviour, Thomas; Palanisamy, Kannan; Hinks, Jamie; Lauro, Federico M; Marsili, Enrico

    2016-12-01

    Low-cost and rapid detection of volatile organic compounds (VOCs) is important for the control of water quality of used water and protection of downstream used water treatment processes. In this work, the effect of sub-toxic concentration of VOCs on the current output of Escherichia coli in bioelectrochemical systems (BES) is shown, in light of environmental sensing applications for sewage and used water networks. E. coli cells were grown on carbon felt electrodes in artificial used water, to increase sensitivity and decrease response time for detection. Extracellular electron transfer was promoted by the addition of a biocompatible redox mediator, 2-hydroxy-1,4-naphthoquinone (HNQ). Among the eight VOCs investigated, toluene is the most toxic to E. coli, with a detection limit of 50±2mgL(-1) and current output of 32±1nAmg(-1)L(-1). This work offers a straightforward route to enhance the detection of organic contaminants in used water for environmental applications. PMID:26947021

  8. Why do co-solvents enhance the solubility of solutes in supercritical fluids? New evidence and opinion.

    PubMed

    Zhang, Xiaogang; Han, Buxing; Hou, Zhenshan; Zhang, Jianling; Liu, Zhimin; Jiang, Tao; He, Jun; Li, Hongping

    2002-11-15

    The effects of two polar co-solvents, chlorodifluoromethane and acetone, on the solubility and enthalpy of a solution of 1,4-naphthoquinone in supercritical (SC) CO2 were studied. We found that the dissolution process becomes less exothermic in the presence of the co-solvents relative to that in pure CO2, although the solubility is enhanced significantly by the co-solvents. This indicates that the increase in the solubility by adding co-solvents results from the increase of the entropy of solution. On the basis of the unexpected results we propose a new mechanism for the solubility enhancement of the solute by the co-solvents in supercritical fluids (SCF); this should be applicable to cases in which the local density of the SC solvent around the solute and the co-solvent is larger, and the co-solvent associates preferentially with the solute. The results are also very important for the understanding of other fundamental questions of SCF science, such as the effect of co-solvents on the thermodynamic and kinetic properties of the reactions in SCFs.

  9. Antibacterial Activity of Juglone against Staphylococcus aureus: From Apparent to Proteomic

    PubMed Central

    Wang, Jiayi; Cheng, Yuhuan; Wu, Rina; Jiang, Donghua; Bai, Bing; Tan, Dehong; Yan, Tingcai; Sun, Xiyun; Zhang, Qi; Wu, Zhaoxia

    2016-01-01

    The proportion of foodborne disease caused by pathogenic microorganisms is rising worldwide, with staphylococcal food poisoning being one of the main causes of this increase. Juglone is a plant-derived 1,4-naphthoquinone with confirmed antibacterial and antitumor activities. However, the specific mechanism underlying its antibacterial activity against Staphylococcus aureus remains unclear. To elucidate the mechanism underlying its antibacterial activity, isobaric tags for relative and absolute quantitation methods of quantitative proteomics were applied for analysis of the 53 proteins that were differentially expressed after treatment with juglone. Combined with verification experiments, such as detection of changes in DNA and RNA content and quantification of oxidative damage, our results suggested that juglone effectively increased the protein expression of oxidoreductase and created a peroxidative environment within the cell, significantly reducing cell wall formation and increasing membrane permeability. We hypothesize that juglone binds to DNA and reduces DNA transcription and replication directly. This is the first study to adopt a proteomic approach to investigate the antibacterial mechanism of juglone. PMID:27322260

  10. Shikonin Inhibits the Proliferation of Human Breast Cancer Cells by Reducing Tumor-Derived Exosomes.

    PubMed

    Wei, Yao; Li, Mingzhen; Cui, Shufang; Wang, Dong; Zhang, Chen-Yu; Zen, Ke; Li, Limin

    2016-01-01

    Shikonin is a naphthoquinone isolated from the traditional Chinese medicine Lithospermum. It has been used in the treatment of various tumors. However, the effects of shikonin on such diseases have not been fully elucidated. In the present study, we detected the exosome release of a breast cancer cell line (MCF-7) with shikonin treatment and found a positive relationship between the level of secreted exosomes and cell proliferation. We next analyzed miRNA profiles in MCF-7 cells and exosomes and found that some miRNAs are specifically sorted and abundant in exosomes. Knockdown of the most abundant miRNAs in exosomes and the MCF-7 proliferation assay showed that miR-128 in exosomes negatively regulates the level of Bax in MCF-7 recipient cells and inhibits cell proliferation. These results show that shikonin inhibits the proliferation of MCF-7 cells through reducing tumor-derived exosomal miR-128. The current study suggests that shikonin suppresses MCF-7 growth by the inhibition of exosome release. PMID:27322220

  11. The phytochemical composition and antioxidant actions of tree nuts.

    PubMed

    Bolling, Bradley W; McKay, Diane L; Blumberg, Jeffrey B

    2010-01-01

    In addition to being a rich source of several essential vitamins and minerals, mono- and polyunsaturated fatty acids, and fiber, most tree nuts provide an array of phytochemicals that may contribute to the health benefits attributed to this whole food. Although many of these constituents remain to be fully identified and characterized, broad classes include the carotenoids, hydrolyzable tannins, lignans, naphthoquinones, phenolic acids, phytosterols, polyphenols, and tocopherols. These phytochemicals have been shown to possess a range of bioactivity, including antioxidant, antiproliferative, anti-inflammatory, antiviral, and hypocholesterolemic properties. This review summarizes the current knowledge of the carotenoid, phenolic, and tocopherol content of tree nuts and associated studies of their antioxidant actions in vitro and in human studies. Tree nuts are a rich source of tocopherols and total phenols and contain a wide variety of flavonoids and proanthocyanidins. In contrast, most tree nuts are not good dietary sources of carotenoids and stilbenes. Phenolic acids are present in tree nuts but a systematic survey of the content and profile of these compounds is lacking. A limited number of human studies indicate these nut phytochemicals are bioaccessible and bioavailable and have antioxidant actions in vivo. PMID:20199996

  12. Conjugated polymer and drug co-encapsulated nanoparticles for Chemo- and Photo-thermal Combination Therapy with two-photon regulated fast drug release

    NASA Astrophysics Data System (ADS)

    Yuan, Youyong; Wang, Zuyong; Cai, Pingqiang; Liu, Jie; Liao, Lun-De; Hong, Minghui; Chen, Xiaodong; Thakor, Nitish; Liu, Bin

    2015-02-01

    The spatial-temporal synchronization of photothermal therapy and chemotherapy is highly desirable for an efficient cancer treatment with synergistic effect. Herein, we developed a chemotherapeutic drug doxorubicin (DOX) and photothermal conjugated polymer (CP) co-loaded nanoplatform using a near-infrared (NIR) laser responsive amphiphilic brush copolymer as the encapsulation matrix. The obtained nanoparticles (NPs) exhibit good monodispersity and excellent stability, which can efficiently convert laser energy into thermal energy for photothermal therapy. Moreover, the hydrophobic polymer matrix bearing a number of 2-diazo-1,2-naphthoquinones (DNQ) moieties could be transformed to a hydrophilic one upon NIR two-photon laser irradiation, which leads to fast drug release. Furthermore, the surface modification of the NPs with cyclic arginine-glycine-aspartic acid (cRGD) tripeptide significantly enhances the accumulation of the NPs within integrin αvβ3 overexpressed cancer cells. The half-maximal inhibitory concentration (IC50) of the combination therapy is 13.7 μg mL-1, while the IC50 for chemotherapy and photothermal therapy alone is 147.8 μg mL-1 and 36.2 μg mL-1, respectively. The combination index (C.I.) is 0.48 (<1), which indicates the synergistic effect for chemotherapy and PTT. These findings provide an excellent NIR laser regulated nanoplatform for combined cancer treatment with synergistic effect due to the synchronous chemo- and photo-thermal therapy.

  13. 2-Phenylaminonaphthoquinones and related compounds: synthesis, trypanocidal and cytotoxic activities.

    PubMed

    Sieveking, Ivan; Thomas, Pablo; Estévez, Juan C; Quiñones, Natalia; Cuéllar, Mauricio A; Villena, Juan; Espinosa-Bustos, Christian; Fierro, Angélica; Tapia, Ricardo A; Maya, Juan D; López-Muñoz, Rodrigo; Cassels, Bruce K; Estévez, Ramon J; Salas, Cristian O

    2014-09-01

    A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds. PMID:25127463

  14. Effect of biogenic photochromic electron acceptors on chlorophyll fluorescence

    NASA Astrophysics Data System (ADS)

    Lobanov, A. V.; Klimenko, I. V.; Nevrova, O. V.; Zhuravleva, T. S.

    2014-05-01

    It is shown that the photophysical properties of chlorophyll a (Chl) depend on the nature and relative amounts of 2-methyl-1,4-naphthoquinone (MNQ) and nicotinamide adenine dinucleotide phosphate (NADP). Photoinduced charge separation occurs in aqueous ethanol solutions of Chl (1 × 10-5 M) and NADP (5 × 10-6-5 × 10-4 M), resulting in the dynamic quenching of Chl fluorescence. Coordination interaction between Chl and NADP is established at an NADP concentration of ≥5 × 10-4 M. The nonlinear Stern-Volmer dependence in this range is due to the input from static quenching. It is shown that the quenching of Chl fluorescence in an MNQ solution at Chl and MNQ concentrations of 1 × 10-5 M and 6.7 × 10-5-1 × 10-4 M, respectively, is described by a linear dependence in the Stern-Volmer coordinates; no complex formation is observed for Chl and MNQ under these conditions, and electron transfer is of the dynamic type. Static or mixed-type energy transfer from MNQ to Chl dominates at elevated MNQ concentrations.

  15. Plumbagin Promotes the Generation of Astrocytes from Rat Spinal Cord Neural Progenitors Via Activation of the Transcription Factor Stat3

    PubMed Central

    Luo, Yongquan; Mughal, Mohamed; Ouyang, Xin; Jiang, Haiyang; Luo, Tae-Gen Son Weiming; Yu, Qian-Sheng; Greig, Nigel H.; Mattson, Mark P.

    2010-01-01

    Plumbagin (5-hydroxy-2-methyl-1,4 naphthoquinone) is a naturally occurring low molecular weight lipophilic phytochemical derived from roots of plants of the Plumbago genus. Plumbagin has been reported to have several clinically relevant biological activities in non-neural cells including antiatherosclerotic, anticoagulant, anticarcinogenic, antitumor and bactericidal effects. In a recent screen of a panel of botanical pesticides we identified plumbagin as having neuroprotective activity. In the present study we determined if plumbagin could modify the developmental fate of rat E14.5 embryonic neural progenitor cells (NPC). Plumbagin exhibited no cytotoxicity when applied to cultured NPC at concentrations below 1 µM. At a concentration of 0.1 µM, plumbagin significantly enhanced the proliferation of NPC as indicated by a 17% increase in the percentage of cells incorporating bromo-deoxyuridine. plumbagin at a concentration of 0.1 pM (but not 0.1 µM), stimulated the production of astrocytes as indicated by increased GFAP expression. Plumbagin selectively induced the proliferation and differentiation of glial progenitor cells without affecting the proliferation or differentiation of neuron-restricted progenitors. Plumbagin (0.1 pM) rapidly activated the transcription factor Stat3 in NPC, and a Stat3 inhibitor peptide prevented both plumbagin-induced astrocyte formation and proliferation. These findings demonstrate the ability of a low molecular weight naturally occurring phytochemical to control the fate of glial progenitor cells by a mechanism involving the Stat3 signaling pathway. PMID:20456019

  16. Microbial fuel cell using anaerobic respiration as an anodic reaction and biomineralized manganese as a cathodic reactant.

    PubMed

    Rhoads, Allison; Beyenal, Haluk; Lewandowski, Zbigniew

    2005-06-15

    We have operated a microbial fuel cell in which glucose was oxidized by Klebsiella pneumoniae in the anodic compartment, and biomineralized manganese oxides, deposited by Leptothrix discophora, were electrochemically reduced in the cathodic compartment. In the anodic compartment, to facilitate the electron transfer from glucose to the graphite electrode, we added a redox mediator, 2-hydroxy-1,4-naphthoquinone. We did not add any redox mediator to the cathodic compartment because the biomineralized manganese oxides were deposited on the surface of a graphite electrode and were reduced directly by electrons from the electrode. We have demonstrated that biomineralized manganese oxides are superiorto oxygen when used as cathodic reactants in microbial fuel cells. The current density delivered by using biomineralized manganese oxides as the cathodic reactant was almost 2 orders of magnitude higher than that delivered using oxygen. Several fuel cells were operated for 500 h, reaching anodic potentials of -441.5 +/- 31 mVscE and cathodic potentials of +384.5 +/- 64 mVscE. When the electrodes were connected by a 50 Ohms resistor, the fuel cell delivered the peak power density of 126.7 +/- 31.5 mW/m2. PMID:16047807

  17. A simple, comprehensive, and miniaturized solvent extraction method for determination of particulate-phase polycyclic aromatic compounds in air.

    PubMed

    Santos, Aldenor G; Regis, Ana Carla D; da Rocha, Gisele O; Bezerra, Marcos de A; de Jesus, Robson M; de Andrade, Jailson B

    2016-02-26

    The method allowed simultaneous characterization of PAHs, nitro-PAHs and quinones in atmospheric particulate matter. This method employs a miniaturized micro-extraction step that uses 500 μL of an acetonitrile-dichloromethane mix and instrumental analysis by means of a high-resolution GC-MS. The method was validated using the SRM1649b NIST standard reference material as well as deuterated internal standards. The results are in good agreement with the certified values and show recoveries between 75% and 145%. Limit of detection (LOD) values for PAHs were found to be between 0.5 pg (benzo[a]pyrene) to 2.1 pg (dibenzo[a,h]anthracene), for nitro-PAHs ranged between 3.2 pg (1-nitrobenzo[e]pyrene) and 22.2 pg (3-nitrophenanthrene), and for quinones ranged between 11.5 pg (1,4-naphthoquinone) and 458 pg (9,10-phenanthraquinone). The validated method was applied to real PM10 samples collected on quartz fiber filters. Concentrations in the PM10 samples ranged from 0.06 to 15 ng m(-3) for PAHs, from

  18. YNL134C from Saccharomyces cerevisiae encodes a novel protein with aldehyde reductase activity for detoxification of furfural derived from lignocellulosic biomass.

    PubMed

    Zhao, Xianxian; Tang, Juan; Wang, Xu; Yang, Ruoheng; Zhang, Xiaoping; Gu, Yunfu; Li, Xi; Ma, Menggen

    2015-05-01

    Furfural and 5-hydroxymethylfurfural (HMF) are the two main aldehyde compounds derived from pentoses and hexoses, respectively, during lignocellulosic biomass pretreatment. These two compounds inhibit microbial growth and interfere with subsequent alcohol fermentation. Saccharomyces cerevisiae has the in situ ability to detoxify furfural and HMF to the less toxic 2-furanmethanol (FM) and furan-2,5-dimethanol (FDM), respectively. Herein, we report that an uncharacterized gene, YNL134C, was highly up-regulated under furfural or HMF stress and Yap1p and Msn2/4p transcription factors likely controlled its up-regulated expression. Enzyme activity assays showed that YNL134C is an NADH-dependent aldehyde reductase, which plays a role in detoxification of furfural to FM. However, no NADH- or NADPH-dependent enzyme activity was observed for detoxification of HMF to FDM. This enzyme did not catalyse the reverse reaction of FM to furfural or FDM to HMF. Further studies showed that YNL134C is a broad-substrate aldehyde reductase, which can reduce multiple aldehydes to their corresponding alcohols. Although YNL134C is grouped into the quinone oxidoreductase family, no quinone reductase activity was observed using 1,2-naphthoquinone or 9,10-phenanthrenequinone as a substrate, and phylogenetic analysis indicates that it is genetically distant to quinone reductases. Proteins similar to YNL134C in sequence from S. cerevisiae and other microorganisms were phylogenetically analysed.

  19. Physicochemical characteristics, oxidative capacities and cytotoxicities of sulfate-coated, 1,4-NQ-coated and ozone-aged black carbon particles

    NASA Astrophysics Data System (ADS)

    Li, Qian; Shang, Jing; Liu, Jia; Xu, Weiwei; Feng, Xiang; Li, Rui; Zhu, Tong

    2015-02-01

    Black carbon (BC) particles play important roles in climate change, visibility impairment, atmospheric reaction process, and health effect. The aging processes of BC alter not only atmospheric composition, but also the physicochemical characteristics of BC itself, thus impacting the environment and health effects. Here, three types of BC including sulfate-coated, 1,4-naphthoquinone (1,4-NQ)-coated, and O3-aged BC are presented. The morphologies, structures, extraction components, the amount of water-soluble organic carbon (WSOC) and free radical intensities of the three types of BC particles are examined by transmission electron microscopy, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), ultraviolet-visible spectrophotometry, total organic carbon detector and electron paramagnetic resonance, respectively. Dithiothreitol (DTT) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assays are utilized to assess the changes in oxidative capacity and cytotoxicity towards murine alveolar macrophage cells. The orders of DTT activities and cytotoxicities of the particles are both arranged as follows: BC/1,4-NQ > BC/O3 > BC > BC/sulfate, mainly because 1,4-NQ owned high oxidative potential and cytotoxicity, while sulfate did not exhibit oxidative capacity and cytotoxicity. The insoluble components of particles contribute most of the total DTT activity, whereas either water or methanol extract is minor contributor. DTT activity was positively correlated with both WSOC content and free radical intensity, with the correlation between DTT activity and WSOC content was stronger than that between DTT activity and free radical intensity.

  20. Nepenthes insignis uses a C2-portion of the carbon skeleton of L-alanine acquired via its carnivorous organs, to build up the allelochemical plumbagin.

    PubMed

    Rischer, Heiko; Hamm, Andreas; Bringmann, Gerhard

    2002-03-01

    Tropical pitcher plants (Nepenthes) catch animals in their specialized cup-shaped leaves, digest the prey by secreting enzymes, and actively take up the resulting compounds. The benefit of this behaviour is the ability to grow and compete in nutrient-poor habitats. Our present in vitro study shows that not only the nitrogen of alanine fed to the carnivorous organs is used by the plant but that in addition intact C2-units derived from C-2 and C-3 of stable isotope labelled L-alanine serve as building blocks, here exemplarily for the synthesis of the secondary metabolite plumbagin, a potent allelochemical. This result adds a new facet to the benefit of carnivory for plants. The availability of plumbagin by a de novo synthesis probably enhances the plants' fitness in their defence against phytophagous and pathogenic organisms. A missing specific uptake or CoA activation mechanism might be the reason that acetate fed to the pitchers was not incorporated into the naphthoquinone plumbagin. The dihydronaphthoquinone glucosides rossoliside and plumbaside A, here isolated for the first time from Nepenthes, by contrast, showed no incorporation after feeding of any of the two precursors, suggesting these compounds to be storage forms with probably very low turnover rates. PMID:11867092

  1. Menaquinone analogs inhibit growth of bacterial pathogens.

    PubMed

    Schlievert, Patrick M; Merriman, Joseph A; Salgado-Pabón, Wilmara; Mueller, Elizabeth A; Spaulding, Adam R; Vu, Bao G; Chuang-Smith, Olivia N; Kohler, Petra L; Kirby, John R

    2013-11-01

    Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four of these organisms to develop novel topical antibacterial agents that interfere with growth and exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, and coenzymes Q1 to Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the growth and to a greater extent exotoxin production of Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, and Streptococcus agalactiae at concentrations of 10 to 200 μg/ml. Coenzyme Q1 reduced the ability of S. aureus to cause toxic shock syndrome in a rabbit model, inhibited the growth of four Gram-negative bacteria, and synergized with another antimicrobial agent, glycerol monolaurate, to inhibit S. aureus growth. The staphylococcal two-component system SrrA/B was shown to be an antibacterial target of coenzyme Q1. We hypothesize that menaquinone analogs both induce toxic reactive oxygen species and affect bacterial plasma membranes and biosynthetic machinery to interfere with two-component systems, respiration, and macromolecular synthesis. These compounds represent a novel class of potential topical therapeutic agents.

  2. Superoxide targets calcineurin signaling in vascular endothelium

    SciTech Connect

    Namgaladze, Dmitry . E-mail: dmitry@zbc.kgu.de; Shcherbyna, Ivanna; Kienhoefer, Joachim; Hofer, H. Werner; Ullrich, Volker

    2005-09-09

    Superoxide emerges as key regulatory molecule in many aspects of vascular physiology and disease, but identification of superoxide targets in the vasculature remains elusive. In this work, we investigated the possibility of inhibition of protein phosphatase calcineurin by superoxide in endothelial cells. We employed a redox cycler 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) to generate superoxide inside the cells. DMNQ caused inhibition of cellular calcineurin phosphatase activity, which was reversible upon DMNQ removal. Inhibition was suppressed by pre-incubating the cells with copper/zinc superoxide dismutase (Cu,ZnSOD). In addition, reducing cellular Cu,ZnSOD activity by diethylthiocarbamic acid treatment resulted in calcineurin inhibition and enhanced sensitivity to DMNQ. Further, we could show that DMNQ inhibits calcineurin-dependent nuclear translocation and transcriptional activation of NFAT transcription factor, and Cu,ZnSOD or superoxide scavenger Tiron reduced the inhibition. Thus, superoxide generation in endothelial cells results in inhibition of calcineurin signaling, which could have important pathophysiological implications in the vasculature.

  3. Exploration of industrially important pigments from soil fungi.

    PubMed

    Akilandeswari, P; Pradeep, B V

    2016-02-01

    The worldwide interest of the current era is to increase tendency towards the use of natural substances instead of synthetic ones. So, alternative and effective environment friendly sustainable technologies are highly needed. Due to a broad range of biological activities, fungi are considered as a significant source of pigments. Among the fungal species in the soil, the genera of Aspergillus, Fusarium, Penicillium, Paecilomyces, and Trichoderma are dominant. The pigments commonly produced by fungi belong to aromatic polyketide groups such as melanins, quinones, flavins, ankaflavin, anthraquinone, and naphthoquinone. The use of fungal pigments has benefits which comprise easy and fast growth in the cheap culture medium and different color shades being independent of weather conditions and would be useful in various industrial applications. In relation to the toxic effects of the synthetic dyes, the natural dyes are easily degradable since they cause no detrimental effects. Thus, the study of pigments produced by soil fungi has tremendous use in medical, textile coloring, food coloring, and cosmetics.

  4. Untargeted MS-based small metabolite identification from the plant leaves and stems of Impatiens balsamina.

    PubMed

    Chua, Lee Suan

    2016-09-01

    The identification of plant metabolites is very important for the understanding of plant physiology including plant growth, development and defense mechanism, particularly for herbal medicinal plants. The metabolite profile could possibly be used for future drug discovery since the pharmacological activities of the indigenous herbs have been proven for centuries. An untargeted mass spectrometric approach was used to identify metabolites from the leaves and stems of Impatiens balsamina using LC-DAD-MS/MS. The putative compounds are mostly from the groups of phenolic, organic and amino acids which are essential for plant growth and as intermediates for other compounds. Alanine appeared to be the main amino acid in the plant because many alanine derived metabolites were detected. There are also several secondary metabolites from the groups of benzopyrones, benzofuranones, naphthoquinones, alkaloids and flavonoids. The widely reported bioactive components such as kaempferol, quercetin and their glycosylated, lawsone and its derivatives were detected in this study. The results also revealed that aqueous methanol could extract flavonoids better than water, and mostly, flavonoids were detected from the leaf samples. The score plots of component analysis show that there is a minor variance in the metabolite profiles of water and aqueous methanolic extracts with 21.5 and 30.5% of the total variance for the first principal component at the positive and negative ion modes, respectively. PMID:27135814

  5. Crystal Structures of the Quinone Oxidoreductase from Thermus thermophilus HB8 and Its Complex with NADPH: Implication for NADPH and Substrate Recognition

    PubMed Central

    Shimomura, Yoshimitsu; Kakuta, Yoshimitsu; Fukuyama, Keiichi

    2003-01-01

    The crystal structures of the ζ-crystalline-like soluble quinone oxidoreductase from Thermus thermophilus HB8 (QORTt) and of its complex with NADPH have been determined at 2.3- and 2.8-Å resolutions, respectively. QORTt is composed of two domains, and its overall fold is similar to the folds of Escherichia coli quinone oxidoreductase (QOREc) and horse liver alcohol dehydrogenase. QORTt forms a homodimer in the crystal by interaction of the βF-strands in domain II, forming a large β-sheet that crosses the dimer interface. High thermostability of QORTt was evidenced by circular dichroic measurement. NADPH is located between the two domains in the QORTt-NADPH complex. The disordered segment involved in the coenzyme binding of apo-QORTt becomes ordered upon NADPH binding. The segment covers an NADPH-binding cleft and may serve as a lid. The 2′-phosphate group of the adenine of NADPH is surrounded by polar and positively charged residues in QORTt, suggesting that QORTt binds NADPH more readily than NADH. The putative substrate-binding site of QORTt, unlike that of QOREc, is largely blocked by nearby residues, permitting access only to small substrates. This may explain why QORTt has weak p-benzoquinone reduction activity and is inactive with such large substrates of QOREc as 5-hydroxy-1,4-naphthoquinone and phenanthraquinone. PMID:12837796

  6. Synthesis, Photochemical and Photoinduced Antibacterial Activity Studies of meso-Tetra(pyren-1-yl)porphyrin and its Ni, Cu and Zn Complexes

    PubMed Central

    Zoltan, Tamara; Vargas, Franklin; Rivas, Carlos; López, Verónica; Perez, Jhackelym; Biasutto, Antonio

    2010-01-01

    The synthesis of the meso-tetra(pyren-1-yl)porphyrin (1) was successfully accomplished by means of the pyrrole condensation with pyrene-1-carb-aldehyde in acidic media. Its metallization was carried out in an almost quantitative yield to obtain the corresponding complexes of Ni(II) (2), Cu(II) (3) and Zn (4). Their photophysical properties such as fluorescence quantum yield and energy transfer to oxygen for an efficient generation of singlet oxygen were determined. Their photophysical and photochemical properties were compared with those of other similar porphyrin derivatives such as tetraphenylporphyrin and tetranaphthylporphyrin. Photochemical studies on their effectiveness as photosensitizer were carried out by means of the photoinduced oxidation of aromatic alcohols like α-naphthol to naphthoquinone. The antibacterial photoactivity assay for compounds 1–4 was testeted against Escherichia coli (ATCC 8739) and its proliferation and viability were measured by chemiluminescence. An efficient inactivation of E. coli was observed. This was more efficient for compounds 2 and 3, following the direct relationship to high generation of singlet oxygen by these compounds. PMID:21179316

  7. Catalytic reaction of cytokinin dehydrogenase: preference for quinones as electron acceptors.

    PubMed Central

    Frébortová, Jitka; Fraaije, Marco W; Galuszka, Petr; Sebela, Marek; Pec, Pavel; Hrbác, Jan; Novák, Ondrej; Bilyeu, Kristin D; English, James T; Frébort, Ivo

    2004-01-01

    The catalytic reaction of cytokinin oxidase/dehydrogenase (EC 1.5.99.12) was studied in detail using the recombinant flavoenzyme from maize. Determination of the redox potential of the covalently linked flavin cofactor revealed a relatively high potential dictating the type of electron acceptor that can be used by the enzyme. Using 2,6-dichlorophenol indophenol, 2,3-dimethoxy-5-methyl-1,4-benzoquinone or 1,4-naphthoquinone as electron acceptor, turnover rates with N6-(2-isopentenyl)adenine of approx. 150 s(-1) could be obtained. This suggests that the natural electron acceptor of the enzyme is quite probably a p-quinone or similar compound. By using the stopped-flow technique, it was found that the enzyme is rapidly reduced by N6-(2-isopentenyl)adenine (k(red)=950 s(-1)). Re-oxidation of the reduced enzyme by molecular oxygen is too slow to be of physiological relevance, confirming its classification as a dehydrogenase. Furthermore, it was established for the first time that the enzyme is capable of degrading aromatic cytokinins, although at low reaction rates. As a result, the enzyme displays a dual catalytic mode for oxidative degradation of cytokinins: a low-rate and low-substrate specificity reaction with oxygen as the electron acceptor, and high activity and strict specificity for isopentenyladenine and analogous cytokinins with some specific electron acceptors. PMID:14965342

  8. Straightforward palladium-mediated synthesis and biological evaluation of benzo[j]phenanthridine-7,12-diones as anti-tuberculosis agents.

    PubMed

    Cappoen, Davie; Jacobs, Jan; Nguyen Van, Tuyen; Claessens, Sven; Diels, Gaston; Anthonissen, Roel; Einarsdottir, Thorbjorg; Fauville, Maryse; Verschaeve, Luc; Huygen, Kris; De Kimpe, Norbert

    2012-02-01

    In 1991, WHO recognized the resurgence of tuberculosis as a global health problem. Although modern chemotherapy is effective against the causative pathogen Mycobacterium tuberculosis, the current drug regimens have failed to eradicate the disease. The success of the pathogen, partially attributed to drug resistance, necessitates the development of novel anti-tuberculosis drugs. Benzo[j]phenanthridine-7,12-diones, tetracyclic derivatives of the natural product benz[g]isoquinoline-5,10-dione, were conveniently synthesized via palladium-catalyzed intramolecular cyclization of N-methanesulfonyl-3-bromo-2-(arylamino)methyl-1,4-naphthoquinones. Here we report on the bioactivity of eight benzo[j]phenanthridine-7,12-dione derivatives as candidate drug molecules against M. tuberculosis and on their cytotoxicity on C3A human hepatocytes. The strongest antimicrobial activity (as detected by growth inhibition of bacteria, using luminometry and BACTEC 460-TB) and lowest cytotoxicity was found for 3-methylbenzo[j]phenanthridine-7,12-dione 5e, which was also effective in targeting intracellular M. tuberculosis (in murine J774 macrophages) and was not genotoxic for C3A hepatocytes.

  9. 2-Sulfanylidene-1,3-dithiolo[4,5-b]naphtho-[2,3-e][1,4]dithiine-5,10-dione.

    PubMed

    Méndez-Rojas, Miguel Angel; Bernès, Sylvain; Pérez-Benítez, Aarón; Romero Zarazúa, María Fernanda; Castellanos-Uribe, Adrián

    2011-11-01

    The title mol-ecule, C(13)H(4)O(2)S(5), is folded by 47.83 (6)° along the S⋯S vector of the [1,4]dithiine six-membered ring, with the naphtho-quinone and [1,3]dithiole-2-thione moieties being nearly planar [largest deviations from least-squares planes = 0.028 (2) and 0.016 (1) Å, respectively]. This boat conformation is close to that observed in the analogous compound [Mendez-Rojas et al. (2001). J. Chem. Crystallogr.31, 17-28] including a 2-oxo group [folding angle: 42.3 (1)° at 213 (2) K]. Both compounds are indeed isomorphous, and the small difference in the folding angle probably results from the involvement of the thioxo group of the title compound in inter-molecular S⋯S contacts [3.5761 (13) Å]. In the crystal structure, mol-ecules are stacked in the [100] direction, with dithiole rings making π-π inter-actions. In a stack, alternating short and long separations are observed between the centroids of dithiole rings, 3.5254 (17) and 4.7010 (18) Å.

  10. Exploration of industrially important pigments from soil fungi.

    PubMed

    Akilandeswari, P; Pradeep, B V

    2016-02-01

    The worldwide interest of the current era is to increase tendency towards the use of natural substances instead of synthetic ones. So, alternative and effective environment friendly sustainable technologies are highly needed. Due to a broad range of biological activities, fungi are considered as a significant source of pigments. Among the fungal species in the soil, the genera of Aspergillus, Fusarium, Penicillium, Paecilomyces, and Trichoderma are dominant. The pigments commonly produced by fungi belong to aromatic polyketide groups such as melanins, quinones, flavins, ankaflavin, anthraquinone, and naphthoquinone. The use of fungal pigments has benefits which comprise easy and fast growth in the cheap culture medium and different color shades being independent of weather conditions and would be useful in various industrial applications. In relation to the toxic effects of the synthetic dyes, the natural dyes are easily degradable since they cause no detrimental effects. Thus, the study of pigments produced by soil fungi has tremendous use in medical, textile coloring, food coloring, and cosmetics. PMID:26701360

  11. Electrochemical study of quinone redox cycling: A novel application of DNA-based biosensors for monitoring biochemical reactions.

    PubMed

    Ensafi, Ali A; Jamei, Hamid Reza; Heydari-Bafrooei, Esmaeil; Rezaei, B

    2016-10-01

    This paper presents the results of an experimental investigation of voltammetric and impedimetric DNA-based biosensors for monitoring biological and chemical redox cycling reactions involving free radical intermediates. The concept is based on associating the amounts of radicals generated with the electrochemical signals produced, using differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). For this purpose, a pencil graphite electrode (PGE) modified with multiwall carbon nanotubes and poly-diallydimethlammonium chloride decorated with double stranded fish sperm DNA was prepared to detect DNA damage induced by the radicals generated from a redox cycling quinone (i.e., menadione (MD; 2-methyl-1,4-naphthoquinone)). Menadione was employed as a model compound to study the redox cycling of quinones. A direct relationship was found between free radical production and DNA damage. The relationship between MD-induced DNA damage and free radical generation was investigated in an attempt to identify the possible mechanism(s) involved in the action of MD. Results showed that DPV and EIS were appropriate, simple and inexpensive techniques for the quantitative and qualitative comparisons of different reducing reagents. These techniques may be recommended for monitoring DNA damages and investigating the mechanisms involved in the production of redox cycling compounds.

  12. A cytotoxic meroterpenoid benzoquinone from roots of Cordia globosa.

    PubMed

    Alencar de Menezes, Jane Eire; Lemos, Telma Leda; Pessoa, Otília Deusdênia; Braz-Filho, Raimundo; Montenegro, Raquel C; Wilke, Diego Veras; Costa-Lotufo, Letícia V; Pessoa, Cláudia; de Moraes, Manoel Odorico; Silveira, Edilberto R

    2005-01-01

    (1a S*,1b S*,7a S*,8a S*)-4,5-Dimethoxy-1a,7a-dimethyl-1,1a,1b,2,7, 7a,8,8a-octahydrocyclopropa cyclopenta[1,2-b]naphthalene-3,6-dione (1), a new meroterpenoid benzoquinone, and microphyllaquinone (2), a known naphthoquinone, have been isolated from roots of Cordia globosa. Both structure determinations were performed by conventional spectroscopic methods, including inverse detection NMR techniques, and by comparison with data from the literature for related compounds. Compound 1 displayed considerable cytotoxic activity against several cancer cell lines with IC50 values in the range of 1.2 to 5.0 microg/mL. The cytotoxic activity seemed to be related to DNA synthesis inhibition, as revealed by the reduction of 5-bromo-2'-deoxyuridine incorporation, and apoptosis induction, as indicated by the acridine orange/ethidium bromide assay and morphological changes after 24 h of incubation on leukemic cells.

  13. Mediators-assisted reductive biotransformation of tetrabromobisphenol-A by Shewanella sp. XB.

    PubMed

    Wang, Jing; Fu, Zhenzhen; Liu, Guangfei; Guo, Ning; Lu, Hong; Zhan, Yaoyao

    2013-08-01

    The anaerobic biotransformation of tetrabromobisphenol A (TBBPA) was mainly observed in the consortia so far. The role of redox mediators in anaerobic TBBPA biotransformation by Shewanella sp. distributed widely in environments was investigated for the first time. The results showed the flavins secretion of Shewanella sp. XB was highly dependent on initial TBBPA concentration. The corresponding first-order rate constants (k) of TBBPA transformation decreased to 0.007 d(-1) when TBBPA concentration increased up to 80 mg/L. Moreover, the removal rate of TBBPA (80 mg/L) was significantly enhanced in treatments amended with cyanocobalamin, riboflavin, 2-hydroxy-1,4-naphthoquinone and Aldrich humic acid with k values of 0.42, 0.19, 0.16, and 0.07 d(-1), respectively. In addition, some redox proteins were secreted and played a role in flavins-mediated extracellular biotransformation of TBBPA by Shewanella sp. XB. These findings are beneficial to better understand TBBPA fate in natural environments and to develop efficient biotreatment strategies of TBBPA pollutions.

  14. Mechanism of action of novel naphthofuranquinones on rat liver microsomal peroxidation.

    PubMed

    Elingold, Igal; Taboas, Melisa I; Casanova, Marta B; Galleano, Mónica; Silva, Raphael S F; Menna-Barreto, Rubem F S; Ventura Pinto, Antonio; de Castro, Solange L; Costa, Lidia E; Dubin, Marta

    2009-12-10

    In order to elucidate the effect on mammal systems of new derivatives from 2-hydroxy-3-allyl-naphthoquinone, alpha-iodinated naphthofuranquinone (NPPN-3223), beta-iodinated naphthofuranquinone (NPPN-3222) and beta-methyl naphthofuranquinone (NPPN-3226) synthesized as possible trypanocidal agents, their effect on rat liver microsomal lipid peroxidation was investigated. They (a) inhibited NADPH-dependent, iron-catalyzed microsomal rat liver lipid peroxidation; (b) did not inhibit the tert-butyl hydroperoxide-dependent lipid peroxidation; (c) did not inhibit ascorbate-lipid peroxidation with the exception of NPPN-3226 which did inhibit it; (d) stimulated NADPH oxidation and microsomal oxygen uptake; (e) increased superoxide anion formation by NADPH-supplemented microsomes and (f) stimulated ascorbate oxidation. The three drugs were reduced to their seminaphthofuranquinone radical by the liver NADPH-P450 reductase system, as detected by ESR measurements. These results support the hypothesis that naphthofuranquinones reduction by microsomal NADPH-P450 reductase and semiquinone oxidation by molecular oxygen diverts electrons, preventing microsomal lipid peroxidation. In addition, hydroquinones and/or semiquinones formed by naphthofuranquinones reduction would be capable of lipid peroxidation inhibition and on interacting with the lipid peroxide radicals can lead to an antioxidant effect as we suggested for NPPN-3226 in close agreement to the inhibition of ascorbate-lipid peroxidation. Due to the properties of these molecules and their incoming structure developments, naphthofuranquinones would be considered as potentially promising therapeutic agents, mainly against Chagas disease. PMID:19744469

  15. Diversity of ABBA Prenyltransferases in Marine Streptomyces sp. CNQ-509: Promiscuous Enzymes for the Biosynthesis of Mixed Terpenoid Compounds

    PubMed Central

    Leipoldt, Franziska; Zeyhle, Philipp; Kulik, Andreas; Kalinowski, Jörn; Heide, Lutz; Kaysser, Leonard

    2015-01-01

    Terpenoids are arguably the largest and most diverse family of natural products, featuring prominently in e.g. signalling, self-defence, UV-protection and electron transfer. Prenyltransferases are essential players in terpenoid and hybrid isoprenoid biosynthesis that install isoprene units on target molecules and thereby often modulate their bioactivity. In our search for new prenyltransferase biocatalysts we focused on the marine-derived Streptomyces sp. CNQ-509, a particularly rich source of meroterpenoid chemistry. Sequencing and analysis of the genome of Streptomyces sp. CNQ-509 revealed seven putative phenol/phenazine-specific ABBA prenyltransferases, and one putative indole-specific ABBA prenyltransferase. To elucidate the substrate specificity of the ABBA prenyltransferases and to learn about their role in secondary metabolism, CnqP1 –CnqP8 were produced in Escherichia coli and incubated with various aromatic and isoprenoid substrates. Five of the eight prenyltransferases displayed enzymatic activity. The efficient conversion of dihydroxynaphthalene derivatives by CnqP3 (encoded by AA958_24325) and the co-location of AA958_24325 with genes characteristic for the biosynthesis of THN (tetrahydroxynaphthalene)-derived natural products indicates that the enzyme is involved in the formation of debromomarinone or other naphthoquinone-derived meroterpenoids. Moreover, CnqP3 showed high flexibility towards a range of aromatic and isoprenoid substrates and thus represents an interesting new tool for biocatalytic applications. PMID:26659564

  16. Vitamin K 3 family members - Part II: Single crystal X-ray structures, temperature-induced packing polymorphism, magneto-structural correlations and probable anti-oncogenic candidature

    NASA Astrophysics Data System (ADS)

    Rane, Sandhya; Ahmed, Khursheed; Salunke-Gawali, Sunita; Zaware, Santosh B.; Srinivas, D.; Gonnade, Rajesh; Bhadbhade, Mohan

    2008-12-01

    Temperature-induced packing polymorphism is observed for vitamin K 3 (menadione, 3-methyl-1,4-naphthoquinone, 1). Form 1a crystallizes at 300 K and 1b at 277 K both in the same space group P2 1/ c. Form 1b contains one molecule per asymmetric unit, performing anisotropy in g-factor viz. g z = 2.0082, g y = 2.0055 and g x = 2.0025, whereas form 1a contains two molecules in its asymmetric unit. Vitamin K 3 family members 2, [2-hydroxy vitamin K 3] and 3, [2-hydroxy-1-oximino vitamin K 3] also perform intrinsic neutral active naphthosemiquinone valence tautomers even in dark having spin concentrations due to hydrogen bonding and aromatic stacking interactions which are compared to vitamin K 3. The significant lateral C-H⋯O and O-H⋯π bifurcated or π-π ∗ interactions are discussed for molecular associations and radical formations. X-ray structure of 3 revealed π-π ∗ stack dimers as radicals signatured in EPR as triplet with five hyperfine splits [ Ā( 14N) = 11.9 G]. The centrosymmetric biradicals in 3 show diamagnetism at high temperature but below 10 K it shows paramagnetism with μeff as 0.19 B.M. Vitamin K 3 and its family members inhibit biological activities of acid phosphatase ( APase), which are proportional to their spin concentrations. This may relate to their probable anti-oncogenic candidature in future.

  17. Synthesis and molecular structure of a zinc complex of the vitamin K3 analogue phthiocol

    NASA Astrophysics Data System (ADS)

    Kathawate, Laxmi; Sproules, Stephen; Pawar, Omkar; Markad, Ganesh; Haram, Santosh; Puranik, Vedavati; Salunke-Gawali, Sunita

    2013-09-01

    The complex [Zn(phthiocol)2(H2O)2]; 1, where phthiocol is 2-hydroxy-3-methyl-1,4-naphthoquinone, has been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-vis spectroscopy, thermogravimetric (TG) analysis, electrochemical and single crystal X-ray diffraction studies. The νCO stretch shifts to lower frequencies upon complexation of phthiocol to Zn2+. 1H NMR spectra show an upfield shift of the benzenoid ring protons in 1. There is a bathochromic shift of the LMCT band in the UV-vis spectra of 1. Single crystal X-ray structure of 1 show distorted octahedral geometry around Zn2+. Two phthiocol ligands are in plane with the metal, while water molecules are trans to this plane. Coordination of deprotonated phthiocol ligands is 'trans, trans' to Zn2+. Intra as well as intermolecular interactions are observed in 1. Molecules of 1 show three dimensional network through CH⋯O and OH⋯O interactions. Additional anodic peaks are observed in cyclic voltammogram of phthiocol ligand due to oxidation of reduced species formed during reduction. One-electron reduction of 1 is shown to be reversible and DFT studies define this redox event as ligand-centered.

  18. Absorption spectrometric and thermodynamic study of charge transfer complexes of menadione (Vitamin K 3) with a series of phenols

    NASA Astrophysics Data System (ADS)

    Pal, Purnendu; Bhattacharya, Sumanta; Mukherjee, Asok K.; Mukherjee, Dulal C.

    2005-03-01

    The electron donor-acceptor (EDA) interactions between menadione (i.e., 2-methyl-1,4-naphthoquinone, which is also called 'Vitamin K 3') and a series of phenols (viz., phenol, resorcinol and p-quinol) have been studied in CCl 4 medium. In all the cases, charge transfer (CT) bands have been located. The CT transition energies ( hνCT) of the complexes are found to change systematically with change in the number and position of the -OH groups in the aromatic ring of the phenol moiety. From the trends in the hνCT values, the Hückel parameters ( hÖ and kC-Ö) for the -OH group have been obtained. The CT transition energies are well correlated with the ionisation potentials of the phenols. From an analysis of this variation the electron affinity of Vitamin K 3 has been found to be 2.28 eV. The stoichiometry of the complexes in each case has been found to be 1(menadione):2 (phenol). Formation constants of the complexes have been determined at four different temperatures from which the enthalpies and entropies of formation of the complexes have been estimated.

  19. Bioprocessing of lignite coals using reductive microorganisms

    SciTech Connect

    Crawford, D.L.

    1989-01-01

    A major goal of this project is to isolate unique microbial strains that catalyze a variety of biochemical transformations of low molecular weight coal substructure model compounds and then to determine if these strains will carry out similar reactions with coal. We have several enrichments underway using suitable model compounds such as pyrogallol (2,3-dihydroxyphenol) and gallic acid (3,4,5-trihydroxybenzoic acid) to isolate organisms that reductively dehydroxylate phenolic hydroxyl groups. We are also using various naphthoquinone and antrhaquinone dyes as substrates in isolation procedures. The most promising results so far are with hydroxynaphthoquinone. The purple non-sulfur bacteria belonging to the genus Rhodobacter are also of interest to us because some of them degrade numerous aromatic compounds by way of reductive pathways. In addition, Rhodobacter species are not sensitive to air. Thus far, enrichment cultures with benzoate have yielded two isolates. Lowering the carboxyl content of lignite coal has been suggested as one means of improving its fuel value. We have isolated a bacterium from soil, tentatively identified as a Bacillus species, that nonoxidatively decarboxylates vanillic acid to guaicol. This bacterium also decarboxylated p-hydroxycinnimates to p-hydroxystyrenes. We are now attempting to get measurable decarboxylation of base-solubilized Vermont lignite coal using this organism. 1 tab.

  20. Plumbagin alters telomere dynamics, induces DNA damage and cell death in human brain tumour cells.

    PubMed

    Khaw, Aik Kia; Sameni, Safoura; Venkatesan, Shriram; Kalthur, Guruprasad; Hande, M Prakash

    2015-11-01

    Natural plant products may possess much potential in palliative therapy and supportive strategies of current cancer treatments with lesser cytotoxicity to normal cells compared to conventional chemotherapy. In the current study, anti-cancer properties of plumbagin, a plant-derived naphthoquinone, on brain cancer cells were determined. Plumbagin treatment resulted in the induction of DNA damage, cell cycle arrest and apoptosis, followed by suppression of the colony forming ability of the brain tumour cells. These effects were substantiated by upregulation of PTEN, TNFRSF1A and downregulation of E2F1 genes, along with a drop in MDM2, cyclin B1, survivin and BCL2 protein expression. Plumbagin induced elevated levels of caspase-3/7 activity as well. For the first time, we show here that plumbagin inhibits telomerase in brain tumour cells and results in telomere shortening following chronic long-term treatment. This observation implies considerable cytotoxicity of plumbagin towards cancer cells with higher telomerase activity. Collectively, our findings suggest plumbagin as a potential chemotherapeutic phytochemical in brain tumour treatment modalities.

  1. Carvacrol and rosemary essential oil manifest cytotoxic, DNA-protective and pro-apoptotic effect having no effect on DNA repair.

    PubMed

    Melusova, M; Slamenova, D; Kozics, K; Jantova, S; Horvathova, E

    2014-01-01

    For several thousand years natural products were successfully used to treat a variety of diseases and to maintain health in humans, but until now it is not fully known what causes these medicinal effects. In our study we assessed the cytotoxic, DNA-protective and pro-apoptotic effect of two frequently occurring natural compounds, carvacrol and rosemary essential oil, on human hepatoma HepG2 cells. In addition we examined the in vitro incision repair activity of liver cell extracts prepared from hepatocytes isolated from Sprague-Dawley (SD) rats fed with water containing carvacrol or rosemary oil. Using conventional and modified single cell gel electrophoresis we proved that incubation of HepG2 cells with selected concentrations of carvacrol and rosemary oil significantly protected cellular DNA against two dangerous oxidative agents, hydrogen peroxide (H(2)O(2)) and 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). It is interesting that despite this DNA protection, the addition of both volatiles to the drinking water of SD rats had no effect on incision repair capacity of hepatocyte extracts. In this paper we also showed that carvacrol and rosemary oil can trigger apoptotic cell death pathways in HepG2 cells, which is probably connected with their cytotoxicity.

  2. The phytochemical composition and antioxidant actions of tree nuts

    PubMed Central

    Bolling, Bradley W; McKay, Diane L; Blumberg, Jeffrey B

    2016-01-01

    In addition to being a rich source of several essential vitamins and minerals, mono- and polyunsaturated fatty acids, and fiber, most tree nuts provide an array of phytochemicals that may contribute to the health benefits attributed to this whole food. Although many of these constituents remain to be fully identified and characterized, broad classes include the carotenoids, hydrolyzable tannins, lignans, naphthoquinones, phenolic acids, phytosterols, polyphenols, and tocopherols. These phytochemicals have been shown to possess a range of bioactivity, including antioxidant, antiproliferative, anti-inflammatory, antiviral, and hypocholesterolemic properties. This review summarizes the current knowledge of the carotenoid, phenolic, and tocopherol content of tree nuts and associated studies of their antioxidant actions in vitro and in human studies. Tree nuts are a rich source of tocopherols and total phenols and contain a wide variety of flavonoids and proanthocyanidins. In contrast, most tree nuts are not good dietary sources of carotenoids and stilbenes. Phenolic acids are present in tree nuts but a systematic survey of the content and profile of these compounds is lacking. A limited number of human studies indicate these nut phytochemicals are bioaccessible and bioavailable and have antioxidant actions in vivo. PMID:20199996

  3. Effects of Salvia officinalis and Thymus vulgaris on oxidant-induced DNA damage and antioxidant status in HepG2 cells.

    PubMed

    Kozics, Katarína; Klusová, Veronika; Srančíková, Annamária; Mučaji, Pavol; Slameňová, Darina; Hunáková, Lubica; Kusznierewicz, Barbara; Horváthová, Eva

    2013-12-01

    Salvia officinalis (SO) and Thymus vulgaris (TV) are medicinal plants well known for their curative powers. However, the molecular mechanisms responsible for these abilities of sage and thyme have not been fully understood yet. In this study we investigated the composition and the quantitative estimation of plant extracts, the protective effects of plant extracts against hydrogen peroxide- and 2,3-dimethoxy-1,4-naphthoquinone-induced DNA damage, and levels of enzymatic and non-enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, glutathione) in human HepG2 cells. To measure antioxidative activity of plant extracts we used three assays: 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). The results showed that the oxidant-induced DNA lesions were significantly reduced in cells pre-treated with the plant extracts studied. The observed DNA-protective activity could be explained by both elevation of GPx activity in cells pre-treated with SO and TV and antioxidant activity of SO and TV.

  4. Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2

    PubMed Central

    Zhang, Zhaoxia; Deng, Wenjun; Kang, Rui; Xie, Min; Billiar, Timothy; Wang, Haichao; Cao, Lizhi; Tang, Daolin

    2016-01-01

    Sepsis is characterized by dysregulated systemic inflammation with release of early (for example, interleukin (IL)-1β) and late (for example, HMGB1) proinflammatory mediators from macrophages. Plumbagin, a medicinal plant-derived naphthoquinone, has been reported to exhibit antiinflammatory activity, but the underling mechanisms remain unclear. Here, we have demonstrated that plumbagin inhibits the inflammatory response through interfering with the immunometabolism pathway in activated macrophages. Remarkably, plumbagin inhibited lipopolysaccharide (LPS)-induced aerobic glycolysis by downregulating the expression of pyruvate kinase M2 (PKM2), a protein kinase responsible for the final and rate-limiting reaction step of the glycolytic pathway. Moreover, the NADPH oxidase 4 (NOX4)-mediated oxidative stress was required for LPS-induced PKM2 expression, because pharmacologic or genetic inhibition of NOX4 by plumbagin or RNA interference limited LPS-induced PKM2 expression, lactate production and subsequent proinflammatory cytokine (IL-1β and HMGB1) release in macrophages. Finally, plumbagin protected mice from lethal endotoxemia and polymicrobial sepsis induced by cecal ligation and puncture. These findings identify a new approach for inhibiting the NOX4/PKM2-dependent immunometabolism pathway in the treatment of sepsis and inflammatory diseases. PMID:26982513

  5. The Combination of Vitamin K3 and Vitamin C Has Synergic Activity against Forms of Trypanosoma cruzi through a Redox Imbalance Process

    PubMed Central

    Cristina Desoti, Vânia; Lazarin-Bidóia, Danielle; Martins Ribeiro, Fabianne; Cardoso Martins, Solange; da Silva Rodrigues, Jean Henrique; Ueda-Nakamura, Tania; Vataru Nakamura, Celso; Farias Ximenes, Valdecir; de Oliveira Silva, Sueli

    2015-01-01

    Chagas’ disease is an infection that is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. Because of severe side effects and variable efficacy, the current treatments for Chagas’ disease are unsatisfactory, making the search for new chemotherapeutic agents essential. Previous studies have reported various biological activities of naphthoquinones, such as the trypanocidal and antitumor activity of vitamin K3. The combination of this vitamin with vitamin C exerted better effects against various cancer cells than when used alone. These effects have been attributed to an increase in reactive oxygen species generation. In the present study, we evaluated the activity of vitamin K3 and vitamin C, alone and in combination, against T. cruzi. The vitamin K3 + vitamin C combination exerted synergistic effects against three forms of T. cruzi, leading to morphological, ultrastructural, and functional changes by producing reactive species, decreasing reduced thiol groups, altering the cell cycle, causing lipid peroxidation, and forming autophagic vacuoles. Our hypothesis is that the vitamin K3 + vitamin C combination induces oxidative imbalance in T. cruzi, probably started by a redox cycling process that leads to parasite cell death. PMID:26641473

  6. Modulatory effects of Tabebuia impetiginosa (Lamiales, Bignoniaceae) on doxorubicin-induced somatic mutation and recombination in Drosophila melanogaster

    PubMed Central

    2009-01-01

    The wing Somatic Mutation and Recombination Test (SMART) in D. melanogaster was used to study genotoxicity of the medicinal plant Tabebuia impetiginosa. Lapachol (naphthoquinone) and β-lapachone (quinone) are the two main chemical constituents of T. impetiginosa. These compounds have several biological properties. They induce apoptosis by generating oxygen-reactive species, thereby inhibiting topoisomerases (I and II) or inducing other enzymes dependent on NAD(P)H:quinone oxidoreductase 1, thus affecting cell cycle checkpoints. The SMART was used in the standard (ST) version, which has normal levels of cytochrome P450 (CYP) enzymes, to check the direct action of this compound, and in the high bioactivation (HB) version, which has a high constitutive level of CYP enzymes, to check for indirect action in three different T. impetiginosa concentrations (10%, 20% or 40% w/w). It was observed that T. impetiginosa alone did not modify the spontaneous frequencies of mutant spots in either cross. The negative results observed prompted us to study this phytotherapeuticum in association with the reference mutagen doxorubicin (DXR). In co-treated series, T. impetiginosa was toxic in both crosses at higher concentration, whereas in the HB cross, it induced a considerable potentiating effect (from ~24.0 to ~95.0%) on DXR genotoxity. Therefore, further research is needed to determine the possible risks associated with the exposure of living organisms to this complex mixture. PMID:21637695

  7. "Subversive" substrates for the enzyme trypanothione disulfide reductase: alternative approach to chemotherapy of Chagas disease.

    PubMed Central

    Henderson, G B; Ulrich, P; Fairlamb, A H; Rosenberg, I; Pereira, M; Sela, M; Cerami, A

    1988-01-01

    The trypanosomatid flavoprotein disulfide reductase, trypanothione reductase, is shown to catalyze one-electron reduction of suitably substituted naphthoquinone and nitrofuran derivatives. A number of such compounds have been chemically synthesized, and a structure-activity relationship has been established; the enzyme is most active with compounds that contain basic functional groups in side-chain residues. The reduced products are readily reoxidized by molecular oxygen and thus undergo classical enzyme-catalyzed redox cycling. In addition to their ability to act as substrates for trypanothione reductase, the compounds are also shown to effectively inhibit enzymatic reduction of the enzyme's physiological substrate, trypanothione disulfide. Under aerobic conditions, trypanothione reductase is not inactivated by these redox-cycling substrates, whereas under anaerobic conditions the nitrofuran compounds cause irreversible inactivation of the enzyme. When tested for biological activity against Trypanosoma cruzi trypomastigotes, many of the test compounds were trypanocidal, and this activity correlated with their relative ability to act as substrates for trypanothione reductase. The activity of the enzyme with these redox-cycling derivatives constitutes a subversion of its normal antioxidant role within the cell. For this reason these compounds may be termed "subversive" substrates for trypanothione reductase. PMID:3135548

  8. Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells

    PubMed Central

    Wiench, Benjamin; Eichhorn, Tolga; Paulsen, Malte; Efferth, Thomas

    2012-01-01

    Chemotherapy is a mainstay of cancer treatment. Due to increased drug resistance and the severe side effects of currently used therapeutics, new candidate compounds are required for improvement of therapy success. Shikonin, a natural naphthoquinone, was used in traditional Chinese medicine for the treatment of different inflammatory diseases and recent studies revealed the anticancer activities of shikonin. We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines. Transcriptome-wide mRNA expression studies showed that shikonin induced genetic pathways regulating cell cycle, mitochondrial function, levels of reactive oxygen species, and cytoskeletal formation. Taking advantage of the inherent fluorescence of shikonin, we analyzed its uptake and distribution in live cells with high spatial and temporal resolution using flow cytometry and confocal microscopy. Shikonin was specifically accumulated in the mitochondria, and this accumulation was associated with a shikonin-dependent deregulation of cellular Ca2+ and ROS levels. This deregulation led to a breakdown of the mitochondrial membrane potential, dysfunction of microtubules, cell-cycle arrest, and ultimately induction of apoptosis. Seeing as both the metabolism and the structure of mitochondria show marked differences between cancer cells and normal cells, shikonin is a promising candidate for the next generation of chemotherapy. PMID:23118796

  9. Decontamination of chemical-warfare agent simulants by polymer surfaces doped with the singlet oxygen generator zinc octaphenoxyphthalocyanine.

    PubMed

    Gephart, Raymond T; Coneski, Peter N; Wynne, James H

    2013-10-23

    Using reactive singlet oxygen (1O2), the oxidation of chemical-warfare agent (CWA) simulants has been demonstrated. The zinc octaphenoxyphthalocyanine (ZnOPPc) complex was demonstrated to be an efficient photosensitizer for converting molecular oxygen (O2) to 1O2 using broad-spectrum light (450-800 nm) from a 250 W halogen lamp. This photosensitization produces 1O2 in solution as well as within polymer matrices. The oxidation of 1-naphthol to naphthoquinone was used to monitor the rate of 1O2 generation in the commercially available polymer film Hydrothane that incorporates ZnOPPc. Using electrospinning, nanofibers of ZnOPPc in Hydrothane and polycarbonate were formed and analyzed for their ability to oxidize demeton-S, a CWA simulant, on the surface of the polymers and were found to have similar reactivity as their corresponding films. The Hydrothane films were then used to oxidize CWA simulants malathion, 2-chloroethyl phenyl sulfide (CEPS), and 2-chloroethyl ethyl sulfide (CEES). Through this oxidation process, the CWA simulants are converted into less toxic compounds, thus decontaminating the surface using only O2 from the air and light.

  10. A solid device based on doped hybrid composites for controlling the dosage of the biocide N-(3-aminopropyl)-N-dodecyl-1,3-propanediamine in industrial formulations.

    PubMed

    Argente-García, A; Muñoz-Ortuño, M; Molins-Legua, C; Moliner-Martínez, Y; Campíns-Falcó, P

    2016-01-15

    A colorimetric composite device is proposed to determine the widely used biocide N-(3-aminopropyl)-N-dodecyl-1,3-propanediamine (ADP).This sensing device is based on a film of 1,2-Naphthoquinone-4-sulfonate (NQS) embedded into polydimethylsiloxane-tetraethylortosilicate-SiO2 nanoparticles composite (PDMS-TEOS-SiO2NPs). Semiquantitative analysis can be performed by visual inspection. Digitalized image or diffuse reflectance (DR) measurements can be carried out for quantitative analysis. Satisfactory detection limit (0.018%, w/v) and relative standard deviations <12% were achieved. The proposed device has been applied for the determination of ADP in detergent industrial formulations with recovery values between 80% and 112%. The method has been successfully validated, showing its high potential to control and monitor this compound because the device is easy to prepare and use, robust, portable, stable over time and cost effective. This device allows a green, simple and rapid approach for the analysis of samples without pretreatment and does not require highly trained personnel. These advantages give the proposed kit good prospects for implementation in several industries. PMID:26592589

  11. [Development and application of electroanalytical methods in biomedical fields].

    PubMed

    Kusu, Fumiyo

    2015-01-01

    To summarize our electroanalytical research in the biomedical field over the past 43 years, this review describes studies on specular reflection measurement, redox potential determination, amperometric acid sensing, HPLC with electrochemical detection, and potential oscillation across a liquid membrane. The specular reflection method was used for clarifying the adsorption of neurotransmitters and their related drugs onto a gold electrode and the interaction between dental alloys and compound iodine glycerin. A voltammetric screening test using a redox potential for the antioxidative effect of flavonoids was proposed. Amperometric acid sensing based on the measurement of the reduction prepeak current of 2-methyl-1,4-naphthoquinone (VK3) or 3,5-di-tert-buty1-1,2-benzoquinone (DBBQ) was applied to determine acid values of fats and oils, titrable acidity of coffee, and enzyme activity of lipase, free fatty acids (FFAs) in serum, short-chain fatty acids in feces, etc. The electrode reactions of phenothiazines, catechins, and cholesterol were applied to biomedical analysis using HPLC with electrochemical detection. A three-channel electrochemical detection system was utilized for the sensitive determination of redox compounds in Chinese herbal medicines. The behavior of barbituric acid derivatives was examined based on potential oscillation measurements.

  12. Surface photochemistry of the herbicide napropamide. The role of the media and environmental factors in directing the fates of intermediates.

    PubMed

    Da Silva, José P; Bastos, Edgar V; Ferreira, Luis F V; Weiss, Richard G

    2008-01-01

    The photochemical behaviour of the herbicide napropamide is studied on cellulose and silica surfaces, using steady-state and laser-flash diffuse reflectance techniques. The results are used to probe how the reaction sites of the host matrices influence the photo-reactive pathways. Napropamide undergoes reaction when irradiated with UV (lamps) or visible (sunlight) radiation on both solid supports. The nature of the intermediates and final products depend strongly on the presence or absence of molecular oxygen. The triplet state of napropamide adsorbed on cellulose is detected by both time-resolved luminescence and transient absorption spectroscopies. The triplet sate was not observed on silica, but transients which include the participation of molecular oxygen are detected during flash photolysis studies. The keto intermediates of the photo-Claisen rearrangement products are observed on both solids. Substituted 1-naphthols from photo-Claisen reactions and 1-naphthol are among the main reaction products. 1,4-Naphthoquinone is a major photoproduct in the presence of molecular oxygen and is expected to be prevalent when napropamide undergoes photodegradation in the environment (i.e., after being applied to plants and fields). PMID:18167599

  13. Chimaphilin induces apoptosis in human breast cancer MCF-7 cells through a ROS-mediated mitochondrial pathway.

    PubMed

    Ma, Wei-Dong; Zou, Yong-Peng; Wang, Peng; Yao, Xiao-Hui; Sun, Yao; Duan, Ming-Hui; Fu, Yu-Jie; Yu, Bo

    2014-08-01

    Chimaphilin, 2,7-dimethyl-1,4-naphthoquinone, is extracted from pyrola [Passiflora incarnata Fisch.]. In this study, the anticancer activity and underlying mechanisms of chimaphilin toward human breast cancer MCF-7 cells are firstly investigated. Chimaphilin could inhibit the viability of MCF-7 cells in a concentration-dependent manner, and the IC50 value was 43.30μM for 24h. Chimaphilin markedly induced apoptosis through the investigation of characteristic apoptotic morphological changes, nuclear DNA fragmentation, annexin V-FITC/propidium iodide (PI) double staining. Flow cytometry assay revealed that chimaphilin triggered a significant generation of ROS and disruption of mitochondrial membrane potential. Additionally, western blotting assay showed that chimaphilin suppressed Bcl-2 level and enhanced Bad level, then activated caspase-9 and caspase-3, and further activated the poly ADP-ribose polymerase (PARP), finally induced cell apoptosis involving the mitochondrial pathway. Furthermore, free radical scavengers N-acetyl-L-cysteine (NAC) pretreatment test testified that chimaphilin could increase the generation of ROS, then induce cell apoptosis. In general, the present results demonstrated that chimaphilin induced apoptosis in human breast cancer MCF-7 cells via a ROS-mediated mitochondrial pathway. PMID:24793375

  14. Shikonin stimulates MC3T3-E1 cell proliferation and differentiation via the BMP-2/Smad5 signal transduction pathway.

    PubMed

    Fang, Tao; Wu, Qianqian; Mu, Shuai; Yang, Liyu; Liu, Shengye; Fu, Qin

    2016-08-01

    Shikonin, the predominant naphthoquinone pigment isolated from the Chinese plant Lithospermum erythrorhizon, is anti‑inflammatory, antiviral and exerts anticancer effects, amongst other biological activities. However, it is unknown whether shikonin affects bone formation. In the present study, the role of shikonin on cell proliferation was assessed via MTT assay, and shikonin was identified to markedly promote cell growth in a time‑ and dose‑dependent manner in the MC3T3‑E1 cell line. In addition, flow cytometric analysis was performed to evaluate the effect of shikonin on the cell cycle, and it was observed that shikonin markedly increased the percentage of S‑phase MC3T3‑E1 cells to accelerate the G1/S transition. To investigate the potential molecular mechanism by which shikonin enhances bone formation, the changes in bone morphogenic protein‑2 (BMP‑2), SMAD family member 5 (Smad5), runt related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin (OC) expression levels induced by shikonin were investigated using western blot analysis and quantitative polymerase chain reaction. The results indicated that shikonin increased the BMP‑2 and Smad5 mRNA levels, and upregulated Smad5 and Runx2 protein expression levels to promote osteoblast differentiation. Furthermore, ALP staining was performed, and revealed that shikonin enhanced ALP activity. These results indicate that shikonin promotes cell proliferation and differentiation of MC3T3-E1 cells via the BMP-2/Smad5 signaling pathway.

  15. Identification of naphthalene metabolism by white rot fungus Armillaria sp. F022.

    PubMed

    Hadibarata, Tony; Yusoff, Abdull Rahim Mohd; Aris, Azmi; Kristanti, Risky Ayu

    2012-01-01

    Armillaria sp. F022, a white rot fungus isolated from tropical rain forest (Samarinda, Indonesia) was used to biodegrade naphthalene in cultured medium. Transformation of naphthalene by Armillaria sp. F022 which is able to use naphthalene, a two ring-polycyclic aromatic hydrocarbon (PAH) as a source of carbon and energy was investigated. The metabolic pathway was elucidated by identifying metabolites, biotransformation studies and monitoring enzyme activities in cell-free extracts. The identification of metabolites suggests that Armillaria sp. F022 initiates its attack on naphthalene by dioxygenation at its C-1 and C-4 positions to give 1,4-naphthoquinone. The intermediate 2-hydroxybenzaldehyde and salicylic acid, and the characteristic of the meta-cleavage of the resulting diol were identified in the long-term incubation. A part from typical metabolites of naphthalene degradation known from mesophiles, benzoic acid was identified as the next intermediate for the naphthalene pathway of this Armillaria sp. F022. Neither phthalic acid, catechol and cis,cis-muconic acid metabolites were detected in culture extracts. Several enzymes (manganese peroxidase, lignin peroxidase, laccase, 1,2-dioxygenase and 2,3-dioxygenase) produced by Armillaria sp. F022 were detected during the incubation.

  16. PLS-Prediction and Confirmation of Hydrojuglone Glucoside as the Antitrypanosomal Constituent of Juglans Spp.

    PubMed

    Ellendorff, Therese; Brun, Reto; Kaiser, Marcel; Sendker, Jandirk; Schmidt, Thomas J

    2015-05-29

    Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found among Juglans spp. (Juglandaceae) with juglone derivatives as known constituents. In this study, 36 highly variable extracts were prepared from different plant parts of J. regia, J. cinerea and J. nigra. For all extracts, antiprotozoal activity was determined against the protozoans Trypanosoma cruzi, T. brucei rhodesiense and Leishmania donovani. In addition, an LC-MS fingerprint was recorded for each extract. With each extract's fingerprint and the data on in vitro growth inhibitory activity against T. brucei rhodesiense a Partial Least Squares (PLS) regression model was calculated in order to obtain an indication of compounds responsible for the differences in bioactivity between the 36 extracts. By means of PLS, hydrojuglone glucoside was predicted as an active compound against T. brucei and consequently isolated and tested in vitro. In fact, the pure compound showed activity against T. brucei at a significantly lower cytotoxicity towards mammalian cells than established antiprotozoal NQs such as lapachol.

  17. Activation of c-Jun N-terminal kinase and apoptosis in endothelial cells mediated by endogenous generation of hydrogen peroxide

    NASA Technical Reports Server (NTRS)

    Ramachandran, Anup; Moellering, Douglas; Go, Young-Mi; Shiva, Sruti; Levonen, Anna-Liisa; Jo, Hanjoong; Patel, Rakesh P.; Parthasarathy, Sampath; Darley-Usmar, Victor M.

    2002-01-01

    Reactive oxygen species have been implicated in the activation of signal transduction pathways. However, extracellular addition of oxidants such as hydrogen peroxide (H2O2) often requires concentrations that cannot be readily achieved under physiological conditions to activate biological responses such as apoptosis. Explanations for this discrepancy have included increased metabolism of H2O2 in the extracellular environment and compartmentalization within the cell. We have addressed this issue experimentally by examining the induction of apoptosis of endothelial cells induced by exogenous addition of H2O2 and by a redox cycling agent, 2,3-dimethoxy-1,4-naphthoquinone, that generates H2O2 in cells. Here we show that low nanomolar steady-state concentrations (0.1-0.5 nmol x min(-1) x 10(6) cells) of H2O2 generated intracellularly activate c-Jun N terminal kinase and initiate apoptosis in endothelial cells. A comparison with bolus hydrogen peroxide suggests that the low rate of intracellular formation of this reactive oxygen species results in a similar profile of activation for both c-Jun N terminal kinase and the initiation of apoptosis. However, a detailed analysis reveals important differences in both the duration and profile for activation of these signaling pathways.

  18. Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis

    PubMed Central

    Djaout, Kamel; Singh, Vinayak; Boum, Yap; Katawera, Victoria; Becker, Hubert F.; Bush, Natassja G.; Hearnshaw, Stephen J.; Pritchard, Jennifer E.; Bourbon, Pauline; Madrid, Peter B.; Maxwell, Anthony; Mizrahi, Valerie; Myllykallio, Hannu; Ekins, Sean

    2016-01-01

    There is an urgent need to identify new treatments for tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (Mtb), which results in 1.5 million deaths each year. We have targeted two essential enzymes in this organism that are promising for antibacterial therapy and reported to be inhibited by naphthoquinones. ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the human enzyme. DNA gyrase is a DNA topoisomerase present in bacteria and plants but not animals. The current study set out to understand the structure-activity relationships of these targets in Mtb using a combination of cheminformatics and in vitro screening. Here, we report the identification of new Mtb ThyX inhibitors, 2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1,4-dihydronaphthalene-1,4-dione) and idebenone, which show modest whole-cell activity and appear to act, at least in part, by targeting ThyX in Mtb. PMID:27283217

  19. Identification of naphthalene metabolism by white rot fungus Armillaria sp. F022.

    PubMed

    Hadibarata, Tony; Yusoff, Abdull Rahim Mohd; Aris, Azmi; Kristanti, Risky Ayu

    2012-01-01

    Armillaria sp. F022, a white rot fungus isolated from tropical rain forest (Samarinda, Indonesia) was used to biodegrade naphthalene in cultured medium. Transformation of naphthalene by Armillaria sp. F022 which is able to use naphthalene, a two ring-polycyclic aromatic hydrocarbon (PAH) as a source of carbon and energy was investigated. The metabolic pathway was elucidated by identifying metabolites, biotransformation studies and monitoring enzyme activities in cell-free extracts. The identification of metabolites suggests that Armillaria sp. F022 initiates its attack on naphthalene by dioxygenation at its C-1 and C-4 positions to give 1,4-naphthoquinone. The intermediate 2-hydroxybenzaldehyde and salicylic acid, and the characteristic of the meta-cleavage of the resulting diol were identified in the long-term incubation. A part from typical metabolites of naphthalene degradation known from mesophiles, benzoic acid was identified as the next intermediate for the naphthalene pathway of this Armillaria sp. F022. Neither phthalic acid, catechol and cis,cis-muconic acid metabolites were detected in culture extracts. Several enzymes (manganese peroxidase, lignin peroxidase, laccase, 1,2-dioxygenase and 2,3-dioxygenase) produced by Armillaria sp. F022 were detected during the incubation. PMID:22894109

  20. A quantitative high-throughput in vitro splicing assay identifies inhibitors of spliceosome catalysis.

    PubMed

    Berg, Michael G; Wan, Lili; Younis, Ihab; Diem, Michael D; Soo, Michael; Wang, Congli; Dreyfuss, Gideon

    2012-04-01

    Despite intensive research, there are very few reagents with which to modulate and dissect the mRNA splicing pathway. Here, we describe a novel approach to identify such tools, based on detection of the exon junction complex (EJC), a unique molecular signature that splicing leaves on mRNAs. We developed a high-throughput, splicing-dependent EJC immunoprecipitation (EJIPT) assay to quantitate mRNAs spliced from biotin-tagged pre-mRNAs in cell extracts, using antibodies to EJC components Y14 and eukaryotic translation initiation factor 4aIII (eIF4AIII). Deploying EJIPT we performed high-throughput screening (HTS) in conjunction with secondary assays to identify splicing inhibitors. We describe the identification of 1,4-naphthoquinones and 1,4-heterocyclic quinones with known anticancer activity as potent and selective splicing inhibitors. Interestingly, and unlike previously described small molecules, most of which target early steps, our inhibitors represented by the benzothiazole-4,7-dione, BN82685, block the second of two trans-esterification reactions in splicing, preventing the release of intron lariat and ligation of exons. We show that BN82685 inhibits activated spliceosomes' elaborate structural rearrangements that are required for second-step catalysis, allowing definition of spliceosomes stalled in midcatalysis. EJIPT provides a platform for characterization and discovery of splicing and EJC modulators. PMID:22252314

  1. Phytochemistry of the carnivorous sundew genus Drosera (Droseraceae) - future perspectives and ethnopharmacological relevance.

    PubMed

    Egan, Paul A; van der Kooy, Frank

    2013-10-01

    Species of the carnivorous genus Drosera L. have long been a source of valuable natural products. The various phytochemicals characteristic of these species, particularly 1,4-naphthoquinones and flavonoids, have contributed to the diverse utilization of sundews in traditional medicine systems worldwide. A growing number of studies have sought to investigate the comparative phytochemistry of Drosera species for improved sources of pharmaceutically important compounds. The outcomes of these studies are here collated, with emergent trends discussed in detail. Important factors which affect production of secondary metabolites in plants are critically examined, such as environmental influences and in vitro culture, and recommendations subsequently presented based on this. Explicitly, the current review aims to i) present an updated, comprehensive listing of the phytochemical constituents of the genus (including quantitative data where available), ii) summarize important factors which may influence the production of phytopharmaceuticals in plants, and iii) recommend guidelines for future research based on the above, including improved standardization and quality control. We have also included a section discussing future perspectives of research on Drosera spp. based on three different research lines i) the potential to produce much needed lead compounds for treatment of tuberculosis, ii) the potential role of anthocyanins in nitrogen transport, and iii) research into 'Natural Deep Eutectic' solvents produced by Drosera spp. in the droplets or 'dew' employed to capture insect prey.

  2. A novel o-naphtoquinone inhibits N-cadherin expression and blocks melanoma cell invasion via AKT signaling.

    PubMed

    Montenegro, Raquel Carvalho; de Vasconcellos, Marne Carvalho; Barbosa, Gleyce Dos Santos; Burbano, Rommel M R; Souza, Luciana G S; Lemos, Telma L G; Costa-Lotufo, Letícia V; de Moraes, Manoel Odorico

    2013-10-01

    The down-regulation or loss of epithelial markers is often accompanied by the up-regulation of mesenchymal markers. E-cadherin generally suppresses invasiveness, whereas N-cadherin promotes invasion and metastasis in vitro. The aim of this work is to investigate the role of biflorin, a naphthoquinone with proven anticancer properties, on the expression of N-cadherin and AKT proteins in MDA-MB-435 invasive melanoma cancer cells after 12h of exposure to 1, 2.5 and 5 μM biflorin. Biflorin inhibited MDA-MB-435 invasion in a dose-dependent manner (p<0.01). Likewise, biflorin down-regulated N-cadherin and AKT-1 expression in a dose-dependent manner. Biflorin did not inhibit the adhesion of MDA-MB-435 cells to any tested substrates. Additionally, biflorin blocked the invasiveness of cells by down-regulating N-cadherin, most likely via AKT-1 signaling. As such, biflorin may be a novel anticancer agent and a new prototype for drug design. PMID:23912027

  3. Echinochrome, a naturally occurring iron chelator and free radical scavenger in artificial and natural membrane systems.

    PubMed

    Lebedev, Alexander V; Ivanova, Marina V; Levitsky, Dmitri O

    2005-01-01

    Echinochrome, or 6-ethyl-2,3,5,7,8-pentahydroxy-1,4-naphthoquinone, possesses cardioprotective activity, and diminishes the myocardial ischemia/reperfusion injury that is known to be accompanied by free-radical oxidative damage and calcium overload. In this study, we investigated the lipophilicity of echinochrome, its ability to inhibit free-radical oxidation both in the bulk organic phase and in an artificial membrane system (liposomes), and to prevent the ferrous/ascorbate-induced leakage of calcium from the isolated sarcoplasmic reticulum (SR) of rabbit skeletal muscle. The experimentally-determined octanol/water partition coefficient (LogP) of echinochrome was +3.11, and the distribution coefficient (LogD) was +2.58 at pH 6.0 and -0.15 at pH 8.0. Echinochrome displayed high scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals with a stoichiometry of about 1:7. Echinochrome was more effective in inhibiting the phosphatidyl choline liposome peroxidation induced by Fe2+/ascorbate than that induced by hemin. The iron chelating ability of echinochrome was estimated spectrophotometrically. In isolated SR, echinochrome protected the ATP-dependent Ca2+-pump system from damage by Fe2+/ascorbate. It was concluded that iron chelation predominates in the overall antioxidant potential of echinochrome. PMID:15589964

  4. A new type of pterocarpanquinone that affects Toxoplasma gondii tachyzoites in vitro.

    PubMed

    Portes, Juliana de Araujo; Netto, Chaquip Daher; da Silva, Alcides José Monteiro; Costa, Paulo Roberto Ribeiro; DaMatta, Renato Augusto; dos Santos, Thiago Alves Teixeira; De Souza, Wanderley; Seabra, Sergio Henrique

    2012-05-25

    Toxoplasma gondii, the agent of Toxoplasmosis, is an obligate intracellular protozoan able to infect a wide range of vertebrate cells, including nonprofessional and professional phagocytes. Therefore, drugs must have intracellular activities in order to control this parasite. The most common therapy for Toxoplasmosis is the combination of sulfadiazine and pyrimethamine. This treatment is associated with adverse reactions, thus, the development of new drugs is necessary. In previous studies, naphthoquinone derivatives showed anti-cancer activity functioning as agents capable of acting on groups of DNA, preventing cancer cells duplication. These derivatives also display anti-parasitic activity against Plasmodium falciparum and Leishmania amazonensis. The derivative pterocarpanquinone tested in this work resulted from the molecular hybridization between pterocarpans and naphtoquinone that presents anti-tumoral and anti-parasitic activities of lapachol. The aim of this work was to determine if this derivative is able to change T. gondii growth within LLC-MK2 cells. The drug did not arrest host cell growth, but was able to decrease the infection index of T. gondii with an IC(50) of 2.5 μM. Scanning and transmission electron microscopy analysis showed morphological changes of parasites including membrane damage. The parasite that survived tended to encyst as seen by Dolichos biflorus lectin staining and Bag-1 expression. These results suggest that pterocarpanquinones are drugs potentially important for the killing and encystment of T. gondii.

  5. Effect of beta-lapachone on superoxide anion and hydrogen peroxide production in Trypanosoma cruzi.

    PubMed Central

    Boveris, A; Docampo, R; Turrens, J F; Stoppani, A O

    1978-01-01

    Addition of beta-lapachone, an o-naphthoquinone endowed with trypanocidal properties to respiring Trypanosoma cruzi epimastigotes induced the release of O2- and H2O2 from the whole cells to the suspending medium. The same beta-lapachone concentration (4 micron) that released H2O2 at maximal rate completely inhibited T. cruzi growth in a liquid medium. The position isomer, alpha-lapachone, did not stimulate O2- and H2O2 release, and did not inhibit epimastigote growth. beta-Lapachone was able to stimulate H2O2 production by the epimastigote homogenate in the presence of NADH as reductant. The same effect was observed with the mitochondrial fraction supplemented with NADH, where beta-lapachone enhanced the generation of O2- and H2O2 4.5- and 2.5-fold respectively. beta-Lapachone also increased O2- and H2O2 production (2.5 and 2-fold respectively) by the microsomal fraction with NADPH as reductant. Cyanide-insensitive NADH and NADPH oxidation by the mitochondrial and microsomal fractions (quinone reductase activity) was stimulated to about the same extent by beta-lapachone. alpha-Lapachone was unable to increase O2- and H2O2 production and quinone reductase activity of the mitochondrial and microsomal fractions. PMID:217340

  6. Untargeted MS-based small metabolite identification from the plant leaves and stems of Impatiens balsamina.

    PubMed

    Chua, Lee Suan

    2016-09-01

    The identification of plant metabolites is very important for the understanding of plant physiology including plant growth, development and defense mechanism, particularly for herbal medicinal plants. The metabolite profile could possibly be used for future drug discovery since the pharmacological activities of the indigenous herbs have been proven for centuries. An untargeted mass spectrometric approach was used to identify metabolites from the leaves and stems of Impatiens balsamina using LC-DAD-MS/MS. The putative compounds are mostly from the groups of phenolic, organic and amino acids which are essential for plant growth and as intermediates for other compounds. Alanine appeared to be the main amino acid in the plant because many alanine derived metabolites were detected. There are also several secondary metabolites from the groups of benzopyrones, benzofuranones, naphthoquinones, alkaloids and flavonoids. The widely reported bioactive components such as kaempferol, quercetin and their glycosylated, lawsone and its derivatives were detected in this study. The results also revealed that aqueous methanol could extract flavonoids better than water, and mostly, flavonoids were detected from the leaf samples. The score plots of component analysis show that there is a minor variance in the metabolite profiles of water and aqueous methanolic extracts with 21.5 and 30.5% of the total variance for the first principal component at the positive and negative ion modes, respectively.

  7. Aqueous extracts of Mozambican plants as alternative and environmentally safe acid-base indicators.

    PubMed

    Macuvele, Domingos Lusitaneo Pier; Sithole, Gerre Zebedias Samo; Cesca, Karina; Macuvele, Suzana Lília Pinare; Matsinhe, Jonas Valente

    2016-06-01

    Indicators are substances that change color as the pH of the medium. Many of these substances are dyes of synthetic origin. The mulala plant (Euclea natalensis), which roots are commonly used by rural communities for their oral hygiene, and roseira (Hibiscus rosa-sinensis), an ornamental plant, are abundant in Mozambique. Currently, synthetic acid-base indicators are most commonly used but have environmental implications and, on the other hand, are expensive products, so the demand for natural indicators started. This study investigated the applicability of aqueous extracts of H. rosa-sinensis and E. natalensis as acid-base indicators. Ground on this work, the extracts can be used as acid-base indicators. On the basis of the absorption spectroscopy in both the UV-Vis region and previous studies, it was possible to preliminarily pinpoint anthocyanins and naphthoquinones as responsible for the shifting of colors depending on the pH range of aqueous extracts of H. rosa-sinensis and E. natalensis. These natural indicators are easily accessible, inexpensive, easy to extract, environmentally safe, and locally available. PMID:26936478

  8. Diversity of ABBA Prenyltransferases in Marine Streptomyces sp. CNQ-509: Promiscuous Enzymes for the Biosynthesis of Mixed Terpenoid Compounds.

    PubMed

    Leipoldt, Franziska; Zeyhle, Philipp; Kulik, Andreas; Kalinowski, Jörn; Heide, Lutz; Kaysser, Leonard

    2015-01-01

    Terpenoids are arguably the largest and most diverse family of natural products, featuring prominently in e.g. signalling, self-defence, UV-protection and electron transfer. Prenyltransferases are essential players in terpenoid and hybrid isoprenoid biosynthesis that install isoprene units on target molecules and thereby often modulate their bioactivity. In our search for new prenyltransferase biocatalysts we focused on the marine-derived Streptomyces sp. CNQ-509, a particularly rich source of meroterpenoid chemistry. Sequencing and analysis of the genome of Streptomyces sp. CNQ-509 revealed seven putative phenol/phenazine-specific ABBA prenyltransferases, and one putative indole-specific ABBA prenyltransferase. To elucidate the substrate specificity of the ABBA prenyltransferases and to learn about their role in secondary metabolism, CnqP1 -CnqP8 were produced in Escherichia coli and incubated with various aromatic and isoprenoid substrates. Five of the eight prenyltransferases displayed enzymatic activity. The efficient conversion of dihydroxynaphthalene derivatives by CnqP3 (encoded by AA958_24325) and the co-location of AA958_24325 with genes characteristic for the biosynthesis of THN (tetrahydroxynaphthalene)-derived natural products indicates that the enzyme is involved in the formation of debromomarinone or other naphthoquinone-derived meroterpenoids. Moreover, CnqP3 showed high flexibility towards a range of aromatic and isoprenoid substrates and thus represents an interesting new tool for biocatalytic applications.

  9. The first naphthosemiquinone complex of K+ with vitamin K3 analog: Experiment and density functional theory

    NASA Astrophysics Data System (ADS)

    Kathawate, Laxmi; Gejji, Shridhar P.; Yeole, Sachin D.; Verma, Prakash L.; Puranik, Vedavati G.; Salunke-Gawali, Sunita

    2015-05-01

    Synthesis and characterization of potassium complex of 2-hydroxy-3-methyl-1,4-naphthoquinone (phthiocol), the vitamin K3 analog, has been carried out using FT-IR, UV-Vis, 1H and 13C NMR, EPR, cyclic voltammetry and single crystal X-ray diffraction experiments combined with the density functional theory. It has been observed that naphthosemiquinone binds to two K+ ions extending the polymeric chain through bridging oxygens O(2) and O(3). The crystal network possesses hydrogen bonding interactions from coordinated water molecules showing water channels along the c-axis. 13C NMR spectra revealed that the complexation of phthiocol with potassium ion engenders deshielding of C(2) signals, which appear at δ = ∼14.6 ppm whereas those of C(3) exhibit up-field signals near δ ∼ 6.9 ppm. These inferences are supported by the M06-2x based density functional theory. Electrochemical experiments further suggest that reduction of naphthosemiquinone results in only a cathodic peak from catechol. A triplet state arising from interactions between neighboring phthiocol anion lead to a half field signal at g = 4.1 in the polycrystalline X-band EPR spectra at 133 K.

  10. Detection of relative [Na+] and [K+] levels in sweat with optical measurements

    NASA Astrophysics Data System (ADS)

    Al-omari, Mahmoud; Sel, Kivanc; Mueller, Anja; Edwards, Jeffery; Kaya, Tolga

    2014-05-01

    We describe the use of 2-hydroxy-1,4-naphthoquinone (HNQ, Lawsone) as a potential sweat electrolyte measurement marker. We use ultraviolet-visible absorbance measurements to determine the absorbance energy in a particular wavelength range (400 nm-500 nm). This novel approach allows us to eliminate the importance of the exact wavelength of the absorbance peak but find the integral of the range of interest. Although we numerically calculate the absorbance energy, it is imperative to use photodiodes to measure the intensity of the transmitted light that is fabricated particularly for the range of interest for future device implementations. We explored various mixing ratios of water and acetone to find the optimum solvent that would give the most sensitive and accurate relative electrolyte sensing. The pH value was also modified to see the effect on the absorbance energy and intensity. A representative group of subjects were used to collect sweat from the dehydration and hyperhydration cases. The results are convincing that HNQ solutions can be used as a wearable, continuous sweat sensor.

  11. A portable optical human sweat sensor

    NASA Astrophysics Data System (ADS)

    Al-omari, Mahmoud; Liu, Gengchen; Mueller, Anja; Mock, Adam; Ghosh, Ruby N.; Smith, Kyle; Kaya, Tolga

    2014-11-01

    We describe the use of HNQ (2-hydroxy-1,4-naphthoquinone or Lawsone) as a potential sweat sensor material to detect the hydration levels of human beings. We have conducted optical measurements using both artificial and human sweat to validate our approach. We have determined that the dominant compound that affects HNQ absorbance in artificial sweat is sodium. The presence of lactate decreases the reactivity of HNQ while urea promotes more interactions of sodium and potassium ions with HNQ. The interactions between the hydroxyl group of HNQ and the artificial sweat components (salts, lactic acid, and urea) were investigated comprehensively. We have also proposed and developed a portable diode laser absorption sensor system that converts the absorbance at a particular wavelength range (at 455 ± 5 nm, where HNQ has an absorbance peak) into light intensity measurements via a photocell. The absorbance intensity values obtained from our portable sensor system agrees within 10.4% with measurements from a laboratory based ultraviolet-visible spectrometer. Findings of this research will provide significant information for researchers who are focusing on real-time, in-situ hydration level detection.

  12. Comparative study of three Plumbago L. species (Plumbaginaceae) by microscopy, UPLC-UV and HPTLC.

    PubMed

    Galal, Ahmed M; Raman, Vijayasankar; Avula, Bharathi; Wang, Yan-Hong; Rumalla, Chidananda Swamy; Weerasooriya, Aruna Dharmapriya; Khan, Ikhlas A

    2013-07-01

    This paper presents a comparative study of anatomy of leaves, stems and roots of three species of Plumbago, namely P. auriculata Lam., P. indica L. and P. zeylanica L. by light microscopy. The paper also provides qualitative and quantitative analysis of the naphthoquinone, plumbagin-a major constituent present in these species-using UPLC-UV. Microscopic examinations revealed the presence of distinctive differences in the anatomical features of the leaf, stem and root of the three species, and these can thus be used for identification and authentication of these species. UPLC-UV analysis showed the highest concentration of plumbagin in the roots of P. zeylanica (1.62% w/w) followed by the roots of P. indica (0.97% w/w) and then P. auriculata (0.33-0.53% w/w). In contrast, plumbagin was not detected in the stems and leaves of P. indica and in the leaves of P. auriculata, whereas very low concentrations (<0.02% w/w) of plumbagin were detected in the stems and leaves of P. zeylanica and in the stems of P. auriculata. HPTLC fingerprints of the leaf and root of the three species exhibited distinguishable profiles, while those of the stems were undifferentiated. PMID:23151906

  13. One-pot synthesis of (-)-oseltamivir and mechanistic insights into the organocatalyzed Michael reaction.

    PubMed

    Mukaiyama, Takasuke; Ishikawa, Hayato; Koshino, Hiroyuki; Hayashi, Yujiro

    2013-12-23

    The one-pot sequential synthesis of (-)-oseltamivir has been achieved without evaporation or solvent exchange in 36% yield over seven reactions. The key step was the asymmetric Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO2 H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo- and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E-Z isomerization of the enamines derived from pentan-3-yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)-N-2-nitroethenylacetamide. The transition-state model for the Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan-3-yloxyacetaldehyde with phenylmaleimide and naphthoquinone.

  14. Characterization of Shikonin Derivative Secretion in Lithospermum erythrorhizon Hairy Roots as a Model of Lipid-Soluble Metabolite Secretion from Plants

    PubMed Central

    Tatsumi, Kanade; Yano, Mariko; Kaminade, Kenta; Sugiyama, Akifumi; Sato, Mayuko; Toyooka, Kiminori; Aoyama, Takashi; Sato, Fumihiko; Yazaki, Kazufumi

    2016-01-01

    Shikonin derivatives are specialized lipophilic metabolites, secreted in abundant amounts from the root epidermal cells of Lithospermum erythrorhizon. Because they have anti-microbial activities, these compounds, which are derivatives of red naphthoquinone, are thought to serve as a chemical barrier for plant roots. The mechanism by which they are secreted from cells is, however, largely unknown. The shikonin production system in L. erythrorhizon is an excellent model for studying the mechanism by which lipophilic compounds are secreted from plant cells, because of the abundant amounts of these compounds produced by L. erythrorhizon, the 0 to 100% inducibility of their production, the light-specific inhibition of production, and the visibility of these products as red pigments. To date, many factors regulating shikonin biosynthesis have been identified, but no mechanism that regulates shikonin secretion without inhibiting biosynthesis has been detected. This study showed that inhibitors of membrane traffic strongly inhibit shikonin secretion without inhibiting shikonin production, suggesting that the secretion of shikonin derivatives into the apoplast utilizes pathways common to the ADP-ribosylation factor/guanine nucleotide exchange factor (ARF/GEF) system and actin filament polymerization, at least in part. These findings provide clues about the machinery involved in secreting lipid-soluble metabolites from cells. PMID:27507975

  15. Evaluation of the effectiveness of an ointment based on Alkannins/Shikonins on second intention wound healing in the dog

    PubMed Central

    Karayannopoulou, Maria; Tsioli, Vassiliki; Loukopoulos, Panayiotis; Anagnostou, Tilemahos L.; Giannakas, Nikolaos; Savvas, Ioannis; Papazoglou, Lysimachos G.; Kaldrymidou, Eleni

    2011-01-01

    The enantiomeric naphthoquinones alkannins and shikonins (A/S) have been established as potent wound healing agents. The purpose of this study was to evaluate the effectiveness of an A/S based ointment for humans on second intention wound healing in the dog, as compared to wound flushing with Lactated Ringer’s solution (LRS). Ten mixed breed dogs, aged 2 to 5 y, were used. One 2.5 × 2.5 cm full-thickness skin defect was created on the lateral aspect of each arm for subjective evaluation, laser-Doppler flowmetry (LDF), and planimetry. Additionally, 3 matching 2 × 2 cm wounds were created on opposite sides of the dorsal midline for histologic evaluation. Wounds were treated once daily with the A/S based ointment on the right side and by flushing with LRS on the left until healed (about 20 d). During the healing process, tissue perfusion (mean LDF value) was found to be significantly higher on the side treated with the A/S based ointment compared with the LRS-treated side. Histologically, angiogenesis (on days 4 and 11), collagen production score (on days 4, 11, and 20), and epithelial thickness score (on day 11) were significantly higher in the wounds treated with the A/S based ointment. Wound size, as evaluated by planimetry, decreased significantly from day 0 to day 20 on both sides, but no significant differences were found between the A/S based ointment and LRS-treated wounds. PMID:21461194

  16. Antifungal and antioxidant activities of the phytomedicine pipsissewa, Chimaphila umbellata.

    PubMed

    Galván, Imelda J; Mir-Rashed, Nadereh; Jessulat, Matthew; Atanya, Monica; Golshani, Ashkan; Durst, Tony; Petit, Philippe; Amiguet, Virginie Treyvaud; Boekhout, Teun; Summerbell, Richard; Cruz, Isabel; Arnason, John T; Smith, Myron L

    2008-02-01

    Bioassay-guided fractionation of Chimaphila umbellata (L.) W. Bart (Pyrolaceae) ethanol extracts led to the identification of 2,7-dimethyl-1,4-naphthoquinone (chimaphilin) as the principal antifungal component. The structure of chimaphilin was confirmed by 1H and 13C NMR spectroscopy. The antifungal activity of chimaphilin was evaluated using the microdilution method with Saccharomyces cerevisiae (0.05mg/mL) and the dandruff-associated fungi Malassezia globosa (0.39mg/mL) and Malassezia restricta (0.55mg/mL). Pronounced antioxidant activity of C. umbellata crude extract was also identified using the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, suggesting this phytomedicine has an antioxidant function in wound healing. A chemical-genetic profile was completed with chimaphilin using approximately 4700 S. cerevisiae gene deletion mutants. Cellular roles of deleted genes in the most susceptible mutants and secondary assays indicate that the targets for chimaphilin include pathways involved in cell wall biogenesis and transcription. PMID:17950387

  17. Cbl participates in shikonin-induced apoptosis by negatively regulating phosphoinositide 3-kinase/protein kinase B signaling.

    PubMed

    Qu, Dan; Xu, Xiao-Man; Zhang, Meng; Jiang, Ting-Shu; Zhang, Yi; Li, Sheng-Qi

    2015-07-01

    Shikonin, a naturally occurring naphthoquinone, exhibits anti-tumorigenic activity. However, its precise mechanisms of action have remained elusive. In the present study, the involvement in the action of shikonin of the ubiquitin ligases Cbl-b and c-Cbl, which are negative regulators of phosphoinositide 3-kinase (PI3K) activation, was investigated. Shikonin was observed to reduce cell viability and induce apoptosis and G2/M phase arrest in lung cancer cells. In addition, shikonin increased the protein levels of B-cell lymphoma 2 (Bcl-2)-associated X and p53 and reduced those of Bcl-2. Additionally, shikonin inhibited PI3k/Akt activity and upregulated Cbl protein expression. In addition, a specific inhibitor of PI3K, LY294002, was observed to have a synergistic effect on the proliferation inhibition and apoptotic induction of A549 cells with shikonin. In conclusion, the results of the present study suggested that Cbl proteins promote shikonin-induced apoptosis by negatively regulating PI3K/Akt signaling in lung cancer cells.

  18. Resistance of Rhizobium strains to phygon, spergon, and thiram.

    PubMed

    Odeyemi, O; Alexander, M

    1977-04-01

    Strains of Rhizobium meliloti, Rhizobium sp. nodulating cowpeas, and R. phaseoli derived from cultures susceptible to tetramethylthiuram disulfide (thiram), 2,3-dichloro-1,4-naphthoquinone (phygon), and 2,3,5,6-tetrachloro-p-benzoquinone (spergon), respectively, grew in the presence of high concentrations of the fungicides and converted them to products not toxic to the sensitive rhizobia. The results of chemical assays demonstrated that the pesticides were destroyed by the resistant bacteria but not by the susceptible parent rhizobia. Resting cells of thiram-metabolizing R. meliloti formed large quantities of dimethyldithiocarbamate, dimethylamine, and CS2 from the pesticide. The products were characterized by gas and thin-layer chromatography, colorimetric reactions, and ultraviolet spectrometry. Dimethylamine and CS2 were formed spontaneously from dimethyldithiocarbamate, but the yield was higher in the presence of R. meliloti. The phygon-resistant bacterium converted the fungicide to five metabolites and thereby rendered the chemical nontoxic to a test fungus. The resistant strain of R. phaseoli generated at least one organic product and released about one-third of the chlorine during its detoxication of spergon.

  19. Resistance of Rhizobium strains to phygon, spergon, and thiram.

    PubMed Central

    Odeyemi, O; Alexander, M

    1977-01-01

    Strains of Rhizobium meliloti, Rhizobium sp. nodulating cowpeas, and R. phaseoli derived from cultures susceptible to tetramethylthiuram disulfide (thiram), 2,3-dichloro-1,4-naphthoquinone (phygon), and 2,3,5,6-tetrachloro-p-benzoquinone (spergon), respectively, grew in the presence of high concentrations of the fungicides and converted them to products not toxic to the sensitive rhizobia. The results of chemical assays demonstrated that the pesticides were destroyed by the resistant bacteria but not by the susceptible parent rhizobia. Resting cells of thiram-metabolizing R. meliloti formed large quantities of dimethyldithiocarbamate, dimethylamine, and CS2 from the pesticide. The products were characterized by gas and thin-layer chromatography, colorimetric reactions, and ultraviolet spectrometry. Dimethylamine and CS2 were formed spontaneously from dimethyldithiocarbamate, but the yield was higher in the presence of R. meliloti. The phygon-resistant bacterium converted the fungicide to five metabolites and thereby rendered the chemical nontoxic to a test fungus. The resistant strain of R. phaseoli generated at least one organic product and released about one-third of the chlorine during its detoxication of spergon. PMID:869529

  20. Acetylshikonin Inhibits Human Pancreatic PANC-1 Cancer Cell Proliferation by Suppressing the NF-κB Activity

    PubMed Central

    Cho, Seok-Cheol; Choi, Bu Young

    2015-01-01

    Acetylshikonin, a natural naphthoquinone derivative compound, has been used for treatment of inflammation and cancer. In the present study, we have investigated whether acetylshikonin could regulate the NF-κB signaling pathway, thereby leading to suppression of tumorigenesis. We observed that acetylshikonin significantly reduced proliferation of several cancer cell lines, including human pancreatic PANC-1 cancer cells. In addition, acetylshikonin inhibited phorbol 12-myristate 13-acetate (PMA) or tumor necrosis-α (TNF-α)-induced NF-κB reporter activity. Proteome cytokine array and real-time RT-PCR results illustrated that acetylshikonin inhibition of PMA-induced production of cytokines was mediated at the transcriptional level and it was associated with suppression of NF-κB activity and matrix metalloprotenases. Finally, we observed that an exposure of acetylshikonin significantly inhibited the anchorage-independent growth of PANC-1 cells. Together, our results indicate that acetylshikonin could serve as a promising therapeutic agent for future treatment of pancreatic cancer. PMID:26336582

  1. Fragmentation studies and electrospray ionization mass spectrometry of lapachol: protonated, deprotonated and cationized species.

    PubMed

    Vessecchi, Ricardo; Emery, Flavio S; Galembeck, Sérgio E; Lopes, Norberto P

    2010-07-30

    Electrospray ionization mass spectrometric analysis of lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) was accomplished in order to elucidate the gas-phase dissociation reactions of this important biologically active natural product. The occurrence of protonated and cationized species in the positive mode and of deprotonated species in the negative mode was explored by means of collision-induced dissociation (CID) experiments. For the protonated molecule, the H(2)O and C(4)H(8) losses occur by two competitive channels. For the deprotonated molecule, the even-electron rule is not conserved, and the radicalar species are eliminated by formation of distonic anions. The fragmentation mechanism for each ion was suggested on the basis of computational thermochemistry. Atomic charges, relative energies, and frontier orbitals were employed aiming at a better understanding of the gas-phase reactivity of lapachol. Potential energy surfaces for fragmentation reactions were obtained by the B3LYP/6-31+G(d,p) model. PMID:20552691

  2. Mitochondrial complex I, aconitase, and succinate dehydrogenase during hypoxia-reoxygenation: modulation of enzyme activities by MnSOD.

    PubMed

    Powell, Charles S; Jackson, Robert M

    2003-07-01

    Both NADH dehydrogenase (complex I) and aconitase are inactivated partially in vitro by superoxide (O2-.) and other oxidants that cause loss of iron from enzyme cubane (4Fe-4S) centers. We tested whether hypoxia-reoxygenation (H-R) by itself would decrease lung epithelial cell NADH dehydrogenase, aconitase, and succinate dehydrogenase (SDH) activities and whether transfection with adenoviral vectors expressing MnSOD (Ad.MnSOD) would inhibit oxidative enzyme inactivation and thus confirm a mechanism involving O2-. Human lung carcinoma cells with alveolar epithelial cell characteristics (A549 cells) were exposed to <1% O2-5% CO2 (hypoxia) for 24 h followed by air-5% CO2 for 24 h (reoxygenation). NADH dehydrogenase activity was assayed in submitochondrial particles; aconitase and SDH activities were measured in cell lysates. H-R significantly decreased NADH dehydrogenase, aconitase, and SDH activities. Ad.MnSOD increased mitochondrial MnSOD substantially and prevented the inhibitory effects of H-R on enzyme activities. Addition of alpha-ketoglutarate plus aspartate, but not succinate, to medium prevented cytotoxicity due to 2,3-dimethoxy-1,4-naphthoquinone. After hypoxia, cells displayed significantly increased dihydrorhodamine fluorescence, indicating increased mitochondrial oxidant production. Inhibition of NADH dehydrogenase, aconitase, and SDH activities during reoxygenation are due to excess O2-. produced in mitochondria, because enzyme inactivation can be prevented by overexpression of MnSOD. PMID:12665464

  3. Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis.

    PubMed

    Djaout, Kamel; Singh, Vinayak; Boum, Yap; Katawera, Victoria; Becker, Hubert F; Bush, Natassja G; Hearnshaw, Stephen J; Pritchard, Jennifer E; Bourbon, Pauline; Madrid, Peter B; Maxwell, Anthony; Mizrahi, Valerie; Myllykallio, Hannu; Ekins, Sean

    2016-01-01

    There is an urgent need to identify new treatments for tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (Mtb), which results in 1.5 million deaths each year. We have targeted two essential enzymes in this organism that are promising for antibacterial therapy and reported to be inhibited by naphthoquinones. ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the human enzyme. DNA gyrase is a DNA topoisomerase present in bacteria and plants but not animals. The current study set out to understand the structure-activity relationships of these targets in Mtb using a combination of cheminformatics and in vitro screening. Here, we report the identification of new Mtb ThyX inhibitors, 2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1,4-dihydronaphthalene-1,4-dione) and idebenone, which show modest whole-cell activity and appear to act, at least in part, by targeting ThyX in Mtb. PMID:27283217

  4. Dihydrodiol dehydrogenase and polycyclic aromatic hydrocarbon metabolism

    SciTech Connect

    Smithgall, T.E.

    1986-01-01

    Carcinogenic activation of polycyclic aromatic hydrocarbons by microsomal monoxygenases proceeds through trans-dihydrodiol metabolites to diol-epoxide ultimate carcinogens. This thesis directly investigated the role of dihydrodiol dehydrogenase, a cytosolic NAD(P)-linked oxidoreductase, in the detoxification of polycyclic aromatic trans-dihydrodiols. A wide variety of non-K-region trans-dihydrodiols were synthesized and shown to be substrates for the homogeneous rat liver dehydrogenase, including several potent proximate carcinogens derived from 7,12-dimethylbenz(a)anthracene, 5-methylchrysene, and benzo(a)pyrene. Since microsomal activation of polycyclic aromatic hydrocarbons is highly stereospecific, the stereochemical course of enzymatic trans-dihydrodiol oxidation was monitored using circular dichroism spectropolarimetry. The major product formed from the dehydrogenase-catalyzed oxidation of the trans-1,2-dihydrodiol of naphthalene was characterized using UV, IR, NMR, and mass spectroscopy, and appears to be 4-hydroxy-1,2-naphthoquinone. Mass spectral analysis suggests that an analogous hydroxylated o-quinone is formed as the major product of benzo(a)pyrene-7,8-dihydrodiol oxidation. Enzymatic oxidation of trans-dihydrodiols was shown to be potently inhibited by all of the major classes of the nonsteroidal antiinflammatory drugs. Enhancement of trans-dihydrodiol proximate carcinogen oxidation may protect against possible adverse effects of the aspirin-like drugs, and help maintain the balance between activation and detoxification of polycyclic aromatic hydrocarbons.

  5. A simple, comprehensive, and miniaturized solvent extraction method for determination of particulate-phase polycyclic aromatic compounds in air.

    PubMed

    Santos, Aldenor G; Regis, Ana Carla D; da Rocha, Gisele O; Bezerra, Marcos de A; de Jesus, Robson M; de Andrade, Jailson B

    2016-02-26

    The method allowed simultaneous characterization of PAHs, nitro-PAHs and quinones in atmospheric particulate matter. This method employs a miniaturized micro-extraction step that uses 500 μL of an acetonitrile-dichloromethane mix and instrumental analysis by means of a high-resolution GC-MS. The method was validated using the SRM1649b NIST standard reference material as well as deuterated internal standards. The results are in good agreement with the certified values and show recoveries between 75% and 145%. Limit of detection (LOD) values for PAHs were found to be between 0.5 pg (benzo[a]pyrene) to 2.1 pg (dibenzo[a,h]anthracene), for nitro-PAHs ranged between 3.2 pg (1-nitrobenzo[e]pyrene) and 22.2 pg (3-nitrophenanthrene), and for quinones ranged between 11.5 pg (1,4-naphthoquinone) and 458 pg (9,10-phenanthraquinone). The validated method was applied to real PM10 samples collected on quartz fiber filters. Concentrations in the PM10 samples ranged from 0.06 to 15 ng m(-3) for PAHs, from

  6. Synthesis of Fe3O4@SiO2@OSi(CH2)3NHRN(CH2PPh2)2PdCl2 type nanocomposite complexes: Highly efficient and magnetically-recoverable catalysts in vitamin K3 synthesis.

    PubMed

    Uruş, Serhan

    2016-12-15

    The synthesis of aminomethylphosphine-metal complexes have opened a new perspective to the catalytic applications of organic compounds. Magnetic Fe3O4 nano-core was synthesized using the closed quartz tube with Teflon cover and microwaved 200°C for 1h with power controlled instrument set to max. 600W. Novel nano-composite supported; Fe3O4@SiO2(CH2)3NHArN(CH2PPh2)2 and Fe3O4@SiO2(CH2)3N(CH2PPh2)2 type bis(diphenylphosphinomethyl)amino ligands and their Pd(II) complexes have been synthesized and characterized with FT-IR, SEM, EDX, TEM, UV-Visible, XRD and TG/DTA techniques. All the complexes were used as heterogeneous catalysts in the oxidation of 2-methyl naphthalene (2MN) to 2-methyl-1, 4-naphthoquinone (vitamin K3, menadione, 2MNQ) in the presence of hydrogen peroxide and acetic acid. Selectivity reached about 55-60% with a conversion of 90-96% using the nano-magnetite supported aminomethylphosphine-Pd(II) complexes. The complexes were very active in three times in the catalytic recycling experiments in five catalytic cycles. PMID:27451189

  7. Characterization of Shikonin Derivative Secretion in Lithospermum erythrorhizon Hairy Roots as a Model of Lipid-Soluble Metabolite Secretion from Plants.

    PubMed

    Tatsumi, Kanade; Yano, Mariko; Kaminade, Kenta; Sugiyama, Akifumi; Sato, Mayuko; Toyooka, Kiminori; Aoyama, Takashi; Sato, Fumihiko; Yazaki, Kazufumi

    2016-01-01

    Shikonin derivatives are specialized lipophilic metabolites, secreted in abundant amounts from the root epidermal cells of Lithospermum erythrorhizon. Because they have anti-microbial activities, these compounds, which are derivatives of red naphthoquinone, are thought to serve as a chemical barrier for plant roots. The mechanism by which they are secreted from cells is, however, largely unknown. The shikonin production system in L. erythrorhizon is an excellent model for studying the mechanism by which lipophilic compounds are secreted from plant cells, because of the abundant amounts of these compounds produced by L. erythrorhizon, the 0 to 100% inducibility of their production, the light-specific inhibition of production, and the visibility of these products as red pigments. To date, many factors regulating shikonin biosynthesis have been identified, but no mechanism that regulates shikonin secretion without inhibiting biosynthesis has been detected. This study showed that inhibitors of membrane traffic strongly inhibit shikonin secretion without inhibiting shikonin production, suggesting that the secretion of shikonin derivatives into the apoplast utilizes pathways common to the ADP-ribosylation factor/guanine nucleotide exchange factor (ARF/GEF) system and actin filament polymerization, at least in part. These findings provide clues about the machinery involved in secreting lipid-soluble metabolites from cells. PMID:27507975

  8. Cytotoxic and antibacterial marfuraquinocins from the deep South China Sea-derived Streptomyces niveus SCSIO 3406.

    PubMed

    Song, Yongxiang; Huang, Hongbo; Chen, Yuchan; Ding, Jie; Zhang, Yun; Sun, Aijun; Zhang, Weimin; Ju, Jianhua

    2013-12-27

    Four new sesquiterpenoid naphthoquinones, marfuraquinocins A-D (1-4), and two new geranylated phenazines, phenaziterpenes A (5) and B (6), were isolated from the fermentation broth of Streptomyces niveus SCSIO 3406, which originated from a South China Sea sediment sample obtained from a depth of 3536 m. The structures of 1-6 were elucidated on the basis of extensive MS and one-dimensional and two-dimensional NMR spectroscopic analyses. In a panel of cytotoxicity and antibacterial assays, 1 and 3 were found to inhibit a NCI-H460 cancer cell line with IC50 values of 3.7 and 4.4 μM, respectively. Compounds 1, 3, and 4 exhibited antibacterial activities against Staphylococcus aureus ATCC 29213 with equivalent MIC values of 8.0 μg/mL; compounds 3 and 4 each showed antibacterial activity against methicillin-resistant Staphylococcus epidermidis (MRSE) shhs-E1 with MIC values of 8.0 μg/mL.

  9. Effects of Salvia officinalis and Thymus vulgaris on oxidant-induced DNA damage and antioxidant status in HepG2 cells.

    PubMed

    Kozics, Katarína; Klusová, Veronika; Srančíková, Annamária; Mučaji, Pavol; Slameňová, Darina; Hunáková, Lubica; Kusznierewicz, Barbara; Horváthová, Eva

    2013-12-01

    Salvia officinalis (SO) and Thymus vulgaris (TV) are medicinal plants well known for their curative powers. However, the molecular mechanisms responsible for these abilities of sage and thyme have not been fully understood yet. In this study we investigated the composition and the quantitative estimation of plant extracts, the protective effects of plant extracts against hydrogen peroxide- and 2,3-dimethoxy-1,4-naphthoquinone-induced DNA damage, and levels of enzymatic and non-enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, glutathione) in human HepG2 cells. To measure antioxidative activity of plant extracts we used three assays: 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). The results showed that the oxidant-induced DNA lesions were significantly reduced in cells pre-treated with the plant extracts studied. The observed DNA-protective activity could be explained by both elevation of GPx activity in cells pre-treated with SO and TV and antioxidant activity of SO and TV. PMID:23870948

  10. New diketopiperazine derivatives from a deep-sea-derived Nocardiopsis alba SCSIO 03039.

    PubMed

    Zhang, Qingbo; Li, Sumei; Chen, Yuchan; Tian, Xinpeng; Zhang, Haibo; Zhang, Guangtao; Zhu, Yiguang; Zhang, Si; Zhang, Weimin; Zhang, Changsheng

    2013-01-01

    The strain SCSIO 03039 was isolated from a sediment sample in the Indian Ocean and was characterized as a Nocardiopsis alba species on the basis of its 16S rRNA gene sequence. Seven diketopiperazines (DKPs), including two new DKPs nocazines D (2a) and E (2b), and five known DKPs (1, 3-6), were isolated from N. alba SCSIO 03039, along with two known compounds 2-methoxy-1,4-naphthoquinone (7) and 1-hydroxy-4-methoxy-2-naphthoic acid (8). Their structures were elucidated by mass and NMR spectroscopic analyses. The structure of methoxyneihumicin (1), previously proposed in a conference poster lacking publicly available experimental data, was validated for the first time by detailed NMR analyses and X-ray diffraction study. The two enantiomers nocazines D (2a) and E (2b) were isolated as a mixture. Compounds 3 and 4 were only known as synthetic compounds before. Methoxyneihumicin (1) exhibited in vitro cytotoxicities against MCF-7 and SF-268 with IC₅₀ values of 4.6 and 12.7 μM, respectively, better than those of 6 (22.0 and 20.6 μM). The other compounds showed less pronounced cytotoxities against three tested human cancer cell lines and no compounds displayed antibacterial activities toward four indicator strains.

  11. Expression Patterns of Glutathione Transferase Gene (GstI) in Maize Seedlings Under Juglone-Induced Oxidative Stress

    PubMed Central

    Sytykiewicz, Hubert

    2011-01-01

    Juglone (5-hydroxy-1,4-naphthoquinone) has been identified in organs of many plant species within Juglandaceae family. This secondary metabolite is considered as a highly bioactive substance that functions as direct oxidant stimulating the production of reactive oxygen species (ROS) in acceptor plants. Glutathione transferases (GSTs, E.C.2.5.1.18) represent an important group of cytoprotective enzymes participating in detoxification of xenobiotics and limiting oxidative damages of cellular macromolecules. The purpose of this study was to investigate the impact of tested allelochemical on growth and development of maize (Zea mays L.) seedlings. Furthermore, the effect of juglone-induced oxidative stress on glutathione transferase (GstI) gene expression patterns in maize seedlings was recorded. It was revealed that 4-day juglone treatment significantly stimulated the transcriptional activity of GstI in maize seedlings compared to control plants. By contrast, at the 6th and 8th day of experiments the expression gene responses were slightly lower as compared with non-stressed seedlings. Additionally, the specific gene expression profiles, as well as the inhibition of primary roots and coleoptile elongation were proportional to juglone concentrations. In conclusion, the results provide strong molecular evidence that allelopathic influence of juglone on growth and development of maize seedlings may be relevant with an induction of oxidative stress in acceptor plants. PMID:22174645

  12. An organic indicator functionalized graphene oxide nanocomposite-based colorimetric assay for the detection of sarcosine

    NASA Astrophysics Data System (ADS)

    Xue, Zhonghua; Yin, Bo; Wang, Hui; Li, Mengqian; Rao, Honghong; Liu, Xiuhui; Zhou, Xinbin; Lu, Xiaoquan

    2016-03-01

    Rapid detection of sarcosine is a key requirement for both diagnosis and treatment of disease. We report here a simple yet sensitive colorimetric nanocomposite platform for rapid detection of sarcosine in alkaline media. The approach exploited the benefits of a rapid color-producing reaction between an organic indicator, 1,2-naphthoquinone-4-sulphonic acid sodium salt (NQS), and the analyte of sarcosine species as well as the good catalytic ability of graphene oxide (GO) to the formation of highly colored products due to its good water dispersibility, extremely large surface area and facile surface modification. As a result, a NQS functionalized GO nanocomposite through π-π stacking has been demonstrated to be useful as a highly efficient catalyst system for the selective and sensitive colorimetric determination of sarcosine by providing a nanocomposite-amplified colorimetric response. Meanwhile, the strategy offered excellent selectivity toward sarcosine species against other amino acids as well as a satisfying detection limit of 0.73 μM. More importantly, by using an electrochemical method, a credible sensing mechanism of GO nanocomposite-based colorimetric platform for a special analyte determination can be easily verified and elucidated, which also provides an attractive alternative to conventional characterization strategies.Rapid detection of sarcosine is a key requirement for both diagnosis and treatment of disease. We report here a simple yet sensitive colorimetric nanocomposite platform for rapid detection of sarcosine in alkaline media. The approach exploited the benefits of a rapid color-producing reaction between an organic indicator, 1,2-naphthoquinone-4-sulphonic acid sodium salt (NQS), and the analyte of sarcosine species as well as the good catalytic ability of graphene oxide (GO) to the formation of highly colored products due to its good water dispersibility, extremely large surface area and facile surface modification. As a result, a NQS

  13. Biopesticides from plants: Calceolaria integrifolia s.l.

    PubMed

    Céspedes, Carlos L; Salazar, Juan R; Ariza-Castolo, Armando; Yamaguchi, Lydia; Avila, José G; Aqueveque, Pedro; Kubo, Isao; Alarcón, Julio

    2014-07-01

    The effects of persistent organic pollutants (POPs) on humans and biodiversity are multiple and varied. Nowadays environmentally-friendly pesticides are strongly preferred to POPs. It is noteworthy that the crop protection role of pesticides and other techniques, i.e. biopesticides, plant extracts, prevention methods, organic methods, evaluation of plant resistance to certain pests under an integrated pest management (IPM), could improve the risks and benefits which must be assessed on a sound scientific basis. For this directive it is crucial to bring about a significant reduction in the use of chemical pesticides, not least through the promotion of sustainable alternative solutions such as organic farming and IPM. Biopesticides are derived from natural materials such as animals, plants, bacteria, and certain minerals. Most of them are biodegradable in relatively short periods of time. On this regard, substances from Calceolaria species emerge as a strong alternative to the use of POPs. The American genus Calceolaria species are regarded both as a notorious weeds and popular ornamental garden plants. Some have medicinal applications. Other taxa of Calceolaria are toxic to insects and resistant to microbial attack. These properties are probably associated with the presence of terpenes, iridoids, flavonoids, naphthoquinones and phenylpropanoids previously demonstrated to have interesting biological activities. In this article a comprehensive evaluation of the potential utilization of Calceolaria species as a source of biopesticides is made. The chemical profile of selected members of the Chilean Calceolaria integrifolia sensu lato complex represents a significant addition to previous studies. New secondary metabolites were isolated, identified and tested for their antifeedant, insect growth regulation and insecticidal activities against Spodoptera frugiperda and Drosophila melanogaster. These species serve as a model of insect pests using conventional procedures

  14. Biopesticides from plants: Calceolaria integrifolia s.l.

    PubMed

    Céspedes, Carlos L; Salazar, Juan R; Ariza-Castolo, Armando; Yamaguchi, Lydia; Avila, José G; Aqueveque, Pedro; Kubo, Isao; Alarcón, Julio

    2014-07-01

    The effects of persistent organic pollutants (POPs) on humans and biodiversity are multiple and varied. Nowadays environmentally-friendly pesticides are strongly preferred to POPs. It is noteworthy that the crop protection role of pesticides and other techniques, i.e. biopesticides, plant extracts, prevention methods, organic methods, evaluation of plant resistance to certain pests under an integrated pest management (IPM), could improve the risks and benefits which must be assessed on a sound scientific basis. For this directive it is crucial to bring about a significant reduction in the use of chemical pesticides, not least through the promotion of sustainable alternative solutions such as organic farming and IPM. Biopesticides are derived from natural materials such as animals, plants, bacteria, and certain minerals. Most of them are biodegradable in relatively short periods of time. On this regard, substances from Calceolaria species emerge as a strong alternative to the use of POPs. The American genus Calceolaria species are regarded both as a notorious weeds and popular ornamental garden plants. Some have medicinal applications. Other taxa of Calceolaria are toxic to insects and resistant to microbial attack. These properties are probably associated with the presence of terpenes, iridoids, flavonoids, naphthoquinones and phenylpropanoids previously demonstrated to have interesting biological activities. In this article a comprehensive evaluation of the potential utilization of Calceolaria species as a source of biopesticides is made. The chemical profile of selected members of the Chilean Calceolaria integrifolia sensu lato complex represents a significant addition to previous studies. New secondary metabolites were isolated, identified and tested for their antifeedant, insect growth regulation and insecticidal activities against Spodoptera frugiperda and Drosophila melanogaster. These species serve as a model of insect pests using conventional procedures

  15. A functional description of CymA, an electron-transfer hub supporting anaerobic respiratory flexibility in Shewanella.

    PubMed

    Marritt, Sophie J; Lowe, Thomas G; Bye, Jordan; McMillan, Duncan G G; Shi, Liang; Fredrickson, Jim; Zachara, John; Richardson, David J; Cheesman, Myles R; Jeuken, Lars J C; Butt, Julea N

    2012-06-15

    CymA (tetrahaem cytochrome c) is a member of the NapC/NirT family of quinol dehydrogenases. Essential for the anaerobic respiratory flexibility of shewanellae, CymA transfers electrons from menaquinol to various dedicated systems for the reduction of terminal electron acceptors including fumarate and insoluble minerals of Fe(III). Spectroscopic characterization of CymA from Shewanella oneidensis strain MR-1 identifies three low-spin His/His co-ordinated c-haems and a single high-spin c-haem with His/H(2)O co-ordination lying adjacent to the quinol-binding site. At pH 7, binding of the menaquinol analogue, 2-heptyl-4-hydroxyquinoline-N-oxide, does not alter the mid-point potentials of the high-spin (approximately -240 mV) and low-spin (approximately -110, -190 and -265 mV) haems that appear biased to transfer electrons from the high- to low-spin centres following quinol oxidation. CymA is reduced with menadiol (E(m) = -80 mV) in the presence of NADH (E(m) = -320 mV) and an NADH-menadione (2-methyl-1,4-naphthoquinone) oxidoreductase, but not by menadiol alone. In cytoplasmic membranes reduction of CymA may then require the thermodynamic driving force from NADH, formate or H2 oxidation as the redox poise of the menaquinol pool in isolation is insufficient. Spectroscopic studies suggest that CymA requires a non-haem co-factor for quinol oxidation and that the reduced enzyme forms a 1:1 complex with its redox partner Fcc3 (flavocytochrome c3 fumarate reductase). The implications for CymA supporting the respiratory flexibility of shewanellae are discussed.

  16. Anaerobic respiration of Escherichia coli in the mouse intestine.

    PubMed

    Jones, Shari A; Gibson, Terri; Maltby, Rosalie C; Chowdhury, Fatema Z; Stewart, Valley; Cohen, Paul S; Conway, Tyrrell

    2011-10-01

    The intestine is inhabited by a large microbial community consisting primarily of anaerobes and, to a lesser extent, facultative anaerobes, such as Escherichia coli, which we have shown requires aerobic respiration to compete successfully in the mouse intestine (S. A. Jones et al., Infect. Immun. 75:4891-4899, 2007). If facultative anaerobes efficiently lower oxygen availability in the intestine, then their sustained growth must also depend on anaerobic metabolism. In support of this idea, mutants lacking nitrate reductase or fumarate reductase have extreme colonization defects. Here, we further explore the role of anaerobic respiration in colonization using the streptomycin-treated mouse model. We found that respiratory electron flow is primarily via the naphthoquinones, which pass electrons to cytochrome bd oxidase and the anaerobic terminal reductases. We found that E. coli uses nitrate and fumarate in the intestine, but not nitrite, dimethyl sulfoxide, or trimethylamine N-oxide. Competitive colonizations revealed that cytochrome bd oxidase is more advantageous than nitrate reductase or fumarate reductase. Strains lacking nitrate reductase outcompeted fumarate reductase mutants once the nitrate concentration in cecal mucus reached submillimolar levels, indicating that fumarate is the more important anaerobic electron acceptor in the intestine because nitrate is limiting. Since nitrate is highest in the absence of E. coli, we conclude that E. coli is the only bacterium in the streptomycin-treated mouse large intestine that respires nitrate. Lastly, we demonstrated that a mutant lacking the NarXL regulator (activator of the NarG system), but not a mutant lacking the NarP-NarQ regulator, has a colonization defect, consistent with the advantage provided by NarG. The emerging picture is one in which gene regulation is tuned to balance expression of the terminal reductases that E. coli uses to maximize its competitiveness and achieve the highest possible population in

  17. From arylamine N-acetyltransferase to folate-dependent acetyl CoA hydrolase: impact of folic acid on the activity of (HUMAN)NAT1 and its homologue (MOUSE)NAT2.

    PubMed

    Laurieri, Nicola; Dairou, Julien; Egleton, James E; Stanley, Lesley A; Russell, Angela J; Dupret, Jean-Marie; Sim, Edith; Rodrigues-Lima, Fernando

    2014-01-01

    Acetyl Coenzyme A-dependent N-, O- and N,O-acetylation of aromatic amines and hydrazines by arylamine N-acetyltransferases is well characterised. Here, we describe experiments demonstrating that human arylamine N-acetyltransferase Type 1 and its murine homologue (Type 2) can also catalyse the direct hydrolysis of acetyl Coenzyme A in the presence of folate. This folate-dependent activity is exclusive to these two isoforms; no acetyl Coenzyme A hydrolysis was found when murine arylamine N-acetyltransferase Type 1 or recombinant bacterial arylamine N-acetyltransferases were incubated with folate. Proton nuclear magnetic resonance spectroscopy allowed chemical modifications occurring during the catalytic reaction to be analysed in real time, revealing that the disappearance of acetyl CH3 from acetyl Coenzyme A occurred concomitantly with the appearance of a CH3 peak corresponding to that of free acetate and suggesting that folate is not acetylated during the reaction. We propose that folate is a cofactor for this reaction and suggest it as an endogenous function of this widespread enzyme. Furthermore, in silico docking of folate within the active site of human arylamine N-acetyltransferase Type 1 suggests that folate may bind at the enzyme's active site, and facilitate acetyl Coenzyme A hydrolysis. The evidence presented in this paper adds to our growing understanding of the endogenous roles of human arylamine N-acetyltransferase Type 1 and its mouse homologue and expands the catalytic repertoire of these enzymes, demonstrating that they are by no means just xenobiotic metabolising enzymes but probably also play an important role in cellular metabolism. These data, together with the characterisation of a naphthoquinone inhibitor of folate-dependent acetyl Coenzyme A hydrolysis by human arylamine N-acetyltransferase Type 1/murine arylamine N-acetyltransferase Type 2, open up a range of future avenues of exploration, both for elucidating the developmental role of these

  18. Potential of herbs in skin protection from ultraviolet radiation.

    PubMed

    Korać, Radava R; Khambholja, Kapil M

    2011-07-01

    Herbs have been used in medicines and cosmetics from centuries. Their potential to treat different skin diseases, to adorn and improve the skin appearance is well-known. As ultraviolet (UV) radiation can cause sunburns, wrinkles, lower immunity against infections, premature aging, and cancer, there is permanent need for protection from UV radiation and prevention from their side effects. Herbs and herbal preparations have a high potential due to their antioxidant activity, primarily. Antioxidants such as vitamins (vitamin C, vitamin E), flavonoids, and phenolic acids play the main role in fighting against free radical species that are the main cause of numerous negative skin changes. Although isolated plant compounds have a high potential in protection of the skin, whole herbs extracts showed better potential due to their complex composition. Many studies showed that green and black tea (polyphenols) ameliorate adverse skin reactions following UV exposure. The gel from aloe is believed to stimulate skin and assist in new cell growth. Spectrophotometer testing indicates that as a concentrated extract of Krameria triandra it absorbs 25 to 30% of the amount of UV radiation typically absorbed by octyl methoxycinnamate. Sesame oil resists 30% of UV rays, while coconut, peanut, olive, and cottonseed oils block out about 20%. A "sclerojuglonic" compound which is forming from naphthoquinone and keratin is the reaction product that provides UV protection. Traditional use of plant in medication or beautification is the basis for researches and making new trends in cosmetics. This review covers all essential aspects of potential of herbs as radioprotective agents and its future prospects.

  19. Conversion of acetyl-coenzyme A into 3-hydroxy-3-methylglutaryl-coenzyme A in radish seedlings. Evidence of a single monomeric protein catalyzing a FeII/quinone-stimulated double condensation reaction.

    PubMed

    Weber, T; Bach, T J

    1994-02-10

    We solubilized from radish membranes and purified to apparent homogeneity a monomeric protein (55.5 kDa) capable of catalyzing the two-step conversion of acetyl-CoA into 3-hydroxy-3-methylglutaryl(HMG)-CoA. Unlike the situation described for other eukaryotes (yeast, animals), both enzyme activities needed for HMG-CoA synthesis (acetoacetyl-CoA thiolase, AACT and HMG-CoA synthase, HMGS) appear to be localized on a single polypeptide. Thus, the enzyme system is further referred to as AACT/HMGS. The reaction as catalyzed by purified AACT/HMGS is strongly stimulated in vitro in presence of FeII-chelates (namely EDTA) and of quinone cofactors with pyrroloquinoline quinone (PQQ) being by far the most effective one studied so far. Whereas the FeII stimulation is apparently due to a Vmax effect, PQQ increases the affinity of the enzyme system towards acetyl-CoA (1.9 microM vs. 5.9 microM, at 50 microM FeII, 100 microM EDTA, 20 microM PQQ). Stimulation by naphthoquinone (NQ) can be overcome in the presence of halogenated NQ-derivatives, while activation by PQQ remains unaffected, possibly indicating a much more specific-binding of the latter cofactor. Gel filtration experiments of enzyme after preincubation in presence of PQQ indicate that there is no covalent-binding of the quinone cofactor to the enzyme. As is also shown with partially purified enzyme from maize membranes, phenylhydrazine, known to react with PQQ as the prosthetic group of quinoproteins (see van der Meer et al. (1987) FEBS Lett. 221, 299-304), efficiently inhibits the reaction. The data lead us to suggest a reaction mechanism that involves radical formation by the redox couple FeII/PQQ, thereby possibly facilitating the energetically unfavorable Claisen condensation as catalyzed during the first partial (AACT) reaction.

  20. Protein Sulfenylation: A Novel Readout of Environmental Oxidant Stress.

    PubMed

    Wages, Phillip A; Lavrich, Katelyn S; Zhang, Zhenfa; Cheng, Wan-Yun; Corteselli, Elizabeth; Gold, Avram; Bromberg, Philip; Simmons, Steven O; Samet, James M

    2015-12-21

    Oxidative stress is a commonly cited mechanism of toxicity of environmental agents. Ubiquitous environmental chemicals such as the diesel exhaust component 1,2-naphthoquinone (1,2-NQ) induce oxidative stress by redox cycling, which generates hydrogen peroxide (H2O2). Cysteinyl thiolate residues on regulatory proteins are subjected to oxidative modification by H2O2 in physiological contexts and are also toxicological targets of oxidant stress induced by environmental contaminants. We investigated whether exposure to environmentally relevant concentrations of 1,2-NQ can induce H2O2-dependent oxidation of cysteinyl thiols in regulatory proteins as a readout of oxidant stress in human airway epithelial cells. BEAS-2B cells were exposed to 0-1000 μM 1,2-NQ for 0-30 min, and levels of H2O2 were measured by ratiometric spectrofluorometry of HyPer. H2O2-dependent protein sulfenylation was measured using immunohistochemistry, immunoblotting, and isotopic mass spectrometry. Catalase overexpression was used to investigate the relationship between H2O2 generation and protein sulfenylation in cells exposed to 1,2-NQ. Multiple experimental approaches showed that exposure to 1,2-NQ at concentrations as low as 3 μM induces H2O2-dependent protein sulfenylation in BEAS-2B cells. Moreover, the time of onset and duration of 1,2-NQ-induced sulfenylation of the regulatory proteins GAPDH and PTP1B showed significant differences. Oxidative modification of regulatory cysteinyl thiols in human lung cells exposed to relevant concentrations of an ambient air contaminant represents a novel marker of oxidative environmental stress.

  1. Cytotoxicity of lawsone and cytoprotective activity of antioxidants in catalase mutant Escherichia coli.

    PubMed

    Sauriasari, Rani; Wang, Da-Hong; Takemura, Yoko; Tsutsui, Ken; Masuoka, Noriyoshi; Sano, Kuniaki; Horita, Masako; Wang, Bing-Ling; Ogino, Keiki

    2007-06-01

    Lawsone is an active naphthoquinone derivative isolated from henna (Lawsonia inermis L.), a widely used hair dye. Previous study on the toxicity of lawsone remains unclear since the involvement of oxidative stress and the kind of ROS (reactive oxygen species) involved have not been fully resolved yet. This present study reports the cytotoxic effects of lawsone and henna. We carried out CAT assay (a zone of inhibition test of bacterial growth and colony-forming efficiency test of transformant Escherichia coli strains that express mammalian catalase gene derived from normal catalase mice (Cs(a)) and catalase-deficient mutant mice (Cs(b))), Ames mutagenicity assay and H(2)O(2) generation assay. Lawsone generated H(2)O(2) slightly in phosphate buffer system and was not mutagenic in Ames assay using TA 98, TA 100 and TA 102, both in the absence and presence of metabolic activation. Lawsone exposure inhibited the growth of both Cs(a) and Cs(b) strains in a dose-dependent manner. Mean zone diameter for Cs(a) was 9.75+/-0.96 mm and 12.75+/-1.5 mm for Cs(b). Natural henna leaves did not show toxic effects, whereas two out of four samples of marketed henna products were shown toxicity effects. Catalase abolished zone of inhibition (ZOI) of marketed henna products, eliminated ZOI of lawsone in a dose-dependent manner and low concentration of exogenous MnSOD and Cu/ZnSOD eliminated the toxicity. Histidine and DTPA, the metal chelator; BHA and low concentration of capsaicin, the inducer of NADH-quinone reductase, effectively protected Cs(a) and Cs(b) against lawsone in this study. We suggest that lawsone cytotoxicity is probably mediated, at least in part, by the release of O(2)(-), H(2)O(2) and OH(-). PMID:17442476

  2. Synthesis and evaluation of the cytotoxic activity of 1,2-furanonaphthoquinones tethered to 1,2,3-1H-triazoles in myeloid and lymphoid leukemia cell lines.

    PubMed

    Cardoso, Mariana F C; Rodrigues, Patrícia C; Oliveira, Maria Eduarda I M; Gama, Ivson L; da Silva, Illana M C B; Santos, Isabela O; Rocha, David R; Pinho, Rosa T; Ferreira, Vitor F; de Souza, Maria Cecília B V; da Silva, Fernando de C; Silva-Jr, Floriano Paes

    2014-09-12

    Leukemia is the most common blood cancer, and its development starts at diverse points, leading to distinct subtypes that respond differently to therapy. This heterogeneity is rarely taken into account in therapies, so it is still essential to look for new specific drugs for leukemia subtypes or even for therapy-resistant cases. Naphthoquinones (NQ) are considered privileged structures in medicinal chemistry due to their plethora of biological activities, including antimicrobial and anticancer effects. Nitrogen-containing heterocycles such as 1,2,3-1H-triazoles have been identified as general scaffolds for generating glycosidase inhibitors. In the present study, the NQ and 1,2,3-1H-triazole cores have been combined to chemically synthesize 18 new 1,2-furanonaphthoquinones tethered to 1,2,3-1H-triazoles (1,2-FNQT). Their cytotoxicities were evaluated against four different leukemia cell lines, including MOLT-4 and CEM (lymphoid cell lines) and K562 and KG1 (myeloid cell lines), as well as normal human peripheral blood mononucleated cells (PBMCs). The new 1,2-FNQT series showed high cytotoxic potential against all leukemia cell lines tested, and some compounds (12o and 12p) showed even better results than the classical therapeutic compounds such as doxorubicin or cisplatin. Others compounds, such as 12b, are promising because of their high selectivity against lymphoblastic leukemia and their low activity against normal hematopoietic cells. The cells of lymphoid origin (MOLT and CEM) were generally more sensitive than the myeloid cell lines to this series of compounds, and most of the compounds that showed the highest cytotoxicity were similarly active against both cell lines.

  3. Formation of environmentally persistent free radicals from the heterogeneous reaction of ozone and polycyclic aromatic compounds.

    PubMed

    Borrowman, Cuyler K; Zhou, Shouming; Burrow, Timothy E; Abbatt, Jonathan P D

    2016-01-01

    In the 1980s long-lived radical species were identified in cigarette tar. Since then, environmentally persistent free radicals (EPFRs) have been observed in ambient particulate matter, and have been generated in particulate matter generated from internal combustion engines. For the first time, we measure in situ the formation and decay of EPFRs through the heterogeneous reaction of ozone and several polycyclic aromatic compounds (PAC). Solid anthracene (ANT), pyrene (PY), benzo[a]pyrene (BAP), benzo[ghi]perylene (BGHIP), 1,4-naphthoquinone (1,4NQ), and 9,10-anthraquinone (AQ) were reacted with gas-phase ozone in a flow system placed in the active cavity of an electron paramagnetic resonance (EPR) spectrometer, and the formation of radicals was measured on the timescale of tens of minutes at ambient levels of ozone down to 30 ppb. For most substrates the net radical production is initially rapid, slows at intermediate times, and is followed by a slow decay. For oxidized solid BAP, radical signal persists for many days in the absence of ozone. To evaluate the effect of substrate phase, the solid PAHs were also dissolved in squalane, an organic oil inert to ozone, which yielded a much higher maximum radical concentration and faster radical decay when exposed to ozone. With higher mobility, reactants were apparently able to more easily diffuse and react with each other, yielding the higher radical concentrations. The EPR spectra exhibit three radicals types, two of which have been assigned to semiquinone species and one to a PAH-derived, carbon-centered radical. Although our system uses levels of PAC not typically found in the environment it is worth noting that the amounts of radical formed, on the order of 10(18) radicals per g, are comparable to those observed in ambient particulate matter.

  4. Tetrathiafulvalene-based mixed-valence acceptor-donor-acceptor triads: a joint theoretical and experimental approach.

    PubMed

    Calbo, Joaquín; Aragó, Juan; Otón, Francisco; Lloveras, Vega; Mas-Torrent, Marta; Vidal-Gancedo, José; Veciana, Jaume; Rovira, Concepció; Ortí, Enrique

    2013-12-01

    This work presents a joint theoretical and experimental characterisation of the structural and electronic properties of two tetrathiafulvalene (TTF)-based acceptor-donor-acceptor triads (BQ-TTF-BQ and BTCNQ-TTF-BTCNQ; BQ is naphthoquinone and BTCNQ is benzotetracyano-p-quinodimethane) in their neutral and reduced states. The study is performed with the use of electrochemical, electron paramagnetic resonance (EPR), and UV/Vis/NIR spectroelectrochemical techniques guided by quantum-chemical calculations. Emphasis is placed on the mixed-valence properties of both triads in their radical anion states. The electrochemical and EPR results reveal that both BQ-TTF-BQ and BTCNQ-TTF-BTCNQ triads in their radical anion states behave as class-II mixed-valence compounds with significant electronic communication between the acceptor moieties. Density functional theory calculations (BLYP35/cc-pVTZ), taking into account the solvent effects, predict charge-localised species (BQ(.-)-TTF-BQ and BTCNQ(.-)-TTF-BTCNQ) as the most stable structures for the radical anion states of both triads. A stronger localisation is found both experimentally and theoretically for the BTCNQ-TTF-BTCNQ anion, in accordance with the more electron-withdrawing character of the BTCNQ acceptor. CASSCF/CASPT2 calculations suggest that the low-energy, broad absorption bands observed experimentally for the BQ-TTF-BQ and BTCNQ-TTF-BTCNQ radical anions are associated with the intervalence charge transfer (IV-CT) electronic transition and two nearby donor-to-acceptor CT excitations. The study highlights the molecular efficiency of the electron-donor TTF unit as a molecular wire connecting two acceptor redox centres.

  5. Shikonin causes cell-cycle arrest and induces apoptosis by regulating the EGFR–NF-κB signalling pathway in human epidermoid carcinoma A431 cells

    PubMed Central

    Tian, Rong; Li, You; Gao, Mei

    2015-01-01

    Shikonin, a naphthoquinone pigment isolated from the Chinese herbal Zicao, has been shown to exhibit antioxidant and anticancer effects. In the present study, we investigated the antiproliferative and pro-apoptotic effects of shikonin on A431 cells and explored the underlying molecular mechanisms. In the present study, our results showed that shikonin significantly inhibited the growth of A431 cells in a concentration- and time-dependent manner, and caused cell cycle arrest by upregulation of p21 and p27, and downregulation of cyclins and cyclin-dependent kinases. In addition, shikonin evidently induced apoptosis due to decreasing Bcl-2 expression, increasing Bax expression, activating caspase and inactivating NF-κB, while pretreatment with a pan-caspase inhibitor Z-Asp-CH2-DCB abrogated shikonin-induced apoptosis. Moreover, EGF could significantly increase the NF-κB DNA-binding activity and reversed the shikonin-induced inactivation of NF-κB. As anticipated AG1478 (EGFR inhibitor) and Bay11-7082 (NF-κB inhibitor) blocked EGF-reversed the inactivation of NF-κB induced by shikonin. Our data also showed that EGF could evidently reverse the shikonin-induced decreases in cell viability and increases in apoptosis. Then, the NF-κB inhibitors such as Bay11-7082, SN50, Helenalin and the EGFR inhibitor AG1478 and its downstream inhibitor such as PI3K inhibitor LY294002 and STAT3 inhibitor Stattic dramatically blocked EGF-reversed decreases in cell viability and increases in apoptosis induced by shikonin. Collectively, our findings indicated that shikonin inhibited cell growth and caused cell cycle arrest of the A431 cells through the regulation of apoptosis. Moreover, these effects were mediated at least partially by suppressing the activation of the EGFR–NF-κB signaling pathways. PMID:25720435

  6. Modeling Bimolecular Reactions and Transport in Porous Media Via Particle Tracking

    SciTech Connect

    Dong Ding; David Benson; Amir Paster; Diogo Bolster

    2012-01-01

    We use a particle-tracking method to simulate several one-dimensional bimolecular reactive transport experiments. In this numerical method, the reactants are represented by particles: advection and dispersion dominate the flow, and molecular diffusion dictates, in large part, the reactions. The particle/particle reactions are determined by a combination of two probabilities dictated by the physics of transport and energetics of reaction. The first is that reactant particles occupy the same volume over a short time interval. The second is the conditional probability that two collocated particles favorably transform into a reaction. The first probability is a direct physical representation of the degree of mixing in an advancing displacement front, and as such lacks empirical parameters except for the user-defined number of particles. This number can be determined analytically from concentration autocovariance, if this type of data is available. The simulations compare favorably to two physical experiments. In one, the concentration of product, 1,2-naphthoquinoe-4-aminobenzene (NQAB) from reaction between 1,2-naphthoquinone-4-sulfonic acid (NQS) and aniline (AN), was measured at the outflow of a column filled with glass beads at different times. In the other, the concentration distribution of reactants (CuSO_4 and EDTA^{4-}) and products (CuEDTA^{4-}) were quantified by snapshots of transmitted light through a column packed with cryloite sand. The thermodynamic rate coefficient in the latter experiment was 10^7 times greater than the former experiment, making it essentially instantaneous. When compared to the solution of the advection-dispersion-reaction equation (ADRE) with the well-mixed reaction coefficient, the experiments and the particle-tracking simulations showed on the order of 20% to 40% less overall product, which is attributed to poor mixing. The poor mixing also leads to higher product concentrations on the edges of the mixing zones, which the particle

  7. Enhancement of DMNQ-induced hepatocyte toxicity by cytochrome P450 inhibition

    SciTech Connect

    Ishihara, Yasuhiro; Shiba, Dai; Shimamoto, Norio . E-mail: n-shimamoto@kph.bunri-u.ac.jp

    2006-07-15

    Two mechanisms have been proposed to explain quinone cytotoxicity: oxidative stress via the redox cycle and the arylation of intracellular nucleophiles. As the redox cycle is catalyzed by NADPH cytochrome P450 reductase, cytochrome P450 systems are expected to be related to the cytotoxicity induced by redox-cycling quinones. Thus, we investigated the relationship between cytochrome P450 systems and quinone toxicity for rat primary hepatocytes using an arylator, 1,4-benzoquinone (BQ), and a redox cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). The hepatocyte toxicity of both BQ and DMNQ increased in a time- and dose-dependent manner. Pretreatment with cytochrome P450 inhibitors, such as SKF-525A (SKF), ketoconazole and 2-methy-1,2-di-3-pyridyl-1-propanone, enhanced the hepatocyte toxicity induced by DMNQ but did not affect BQ-induced hepatocyte toxicity. The production of superoxide anion and the levels of glutathione disulfide and thiobarbituric-acid-reactive substances were increased by treatment with DMNQ, and SKF pretreatment further enhanced their increases. In addition, NADPH oxidation in microsomes was increased by treatment with DMNQ and further augmented by pretreatment with SKF, and a NADPH cytochrome P450 reductase inhibitor, diphenyleneiodonium chloride completely suppressed NADPH oxidations increased by treatment with either DMNQ- or DMNQ + SKF. Pretreatment with antioxidants, such as {alpha}-tocopherol, reduced glutathione, N-acetyl cysteine or an iron ion chelator deferoxamine, totally suppressed DMNQ- and DMNQ + SKF-induced hepatocyte toxicity. These results indicate that the hepatocyte toxicity of redox-cycling quinones is enhanced under cytochrome P450 inhibition, and that this enhancement is caused by the potentiation of oxidative stress.

  8. Modification of bone marrow radiosensensitivity by medicinal plant extracts.

    PubMed

    Ganasoundari, A; Zare, S M; Devi, P U

    1997-06-01

    Withaferin A (WA), a steroidal lactone, and Plumbagin (Pl), a naphthoquinone, from the roots of Withania somnifera and Plumbago rosea, respectively, have been shown to possess growth inhibitory and radiosensitizing effects on experimental mouse tumours. An aqueous extract of the leaves of Ocimum sanctum (OE) was found to protect mice against radiation lethality. Therefore, the radiomodifying effects of the above plant products on the bone marrow of the adult Swiss mouse was studied. Single doses of WA (30 mg kg-1) or Pl (5 mg kg-1) were injected intraperitoneally (ip) and OE (10 mg kg-1) was injected ip once daily for five consecutive days. Administration of extracts was followed by 2 Gy whole body gamma irradiation. Bone marrow stem cell survival was studied by an exogenous spleen colony unit (CFU-S) assay. The effects of WA and Pl were compared with that of cyclophosphamide (CP) and radioprotection by OE was compared with that of WR-2721 (WR). Radiation reduced the CFU-S to less than 50% of normal. WA, CP and Pl significantly enhanced this effect and reduced the CFU-S to almost the same extent (to < 20% of normal), although individually WA and Pl were less cytotoxic than CP. These results indicate that radiosensitization by WA and Pl is not tumour specific. OE significantly increased CFU-S compared with radiotherapy (RT) alone. OE+RT gave a higher stem cell survival (p < 0.05) than that produced by WR+RT. While WR alone had a toxic effect, OE treatment showed no such effect, suggesting that the latter may have an advantage over WR in clinical application. PMID:9227253

  9. Polycyclic aromatic hydrocarbons (PAHs) and their derivatives (oxygenated-PAHs, nitrated-PAHs and azaarenes) in size-fractionated particles emitted in an urban road tunnel

    NASA Astrophysics Data System (ADS)

    Alves, C. A.; Vicente, A. M. P.; Gomes, J.; Nunes, T.; Duarte, M.; Bandowe, B. A. M.

    2016-11-01

    A sampling campaign of size segregated particulate matter (PM0.5, PM0.5-1, PM1-2.5 and PM2.5-10) was carried out at two sites, one in a road tunnel (Braga, Portugal) and another at an urban background location in the neighbourhood. Particle-bound polycyclic aromatic compounds were extracted with organic solvents and analysed by gas chromatography-mass spectrometry. Twenty six parent and alkyl-polycyclic aromatic hydrocarbons (PAHs), 4 azaarenes (AZAs), 15 nitrated and 15 oxygenated derivatives (NPAHs and OPAHs) were analysed. On average, submicron particles (PM1) in the tunnel comprised 93, 91, 96 and 71% of the total PAHs, OPAHs, NPAHs and AZAs mass in PM10, respectively. Tunnel to outdoor PAH concentration ratios between 10 and 14 reveal the strong contribution of fresh exhaust emissions to the PM loads. The dominant PAHs in the tunnel were pyrene, retene and benzo[ghi]perylene, accounting for 20, 17 and 8% of the total PAH levels in PM10, respectively. Isomer ratios indicated the importance of unburnt fuel as a significant PAH source. The only NPAH consistently present in all samples was 5-nitroacenaphthene. Indanone and 1,8-naphthalic anhydride were the most abundant OPAHs, accounting for 25 and 17% of the total concentrations of this organic class, respectively. Other abundant OPAHs were 1,4-naphthoquinone, 9-fluorenone, 1,2-acenaphthylenequinone and 7H-benz[de]anthracene-7-one. Individual emission factors (μg veh- 1 km- 1) were estimated and compared with those obtained in other tunnel studies.

  10. Plumbagin induces cell death through a copper-redox cycle mechanism in human cancer cells.

    PubMed

    Nazeem, S; Azmi, Asfar S; Hanif, Sarmad; Ahmad, Aamir; Mohammad, Ramzi M; Hadi, S M; Kumar, K Sateesh

    2009-09-01

    Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica has been shown to exert anticancer and anti-proliferative activities in cells in culture as well as animal tumor models. In our previous paper, we have reported the cytotoxic action of plumbagin in plasmid pBR322 DNA as well as human peripheral blood lymphocytes through a redox mechanism involving copper. Copper has been shown to be capable of mediating the action of several plant-derived compounds through production of reactive oxygen species (ROS). The objective of the present study was to determine whether plumbagin induces apoptosis in human cancer cells through the same mechanism which we proposed earlier. Using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, 3-(4,5-B-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell growth inhibition, histone/DNA ELISA, homogeneous caspase-3/7 assay for apoptosis as well as alkaline comet assay for DNA single-strand breaks detection in this report, we confirm that plumbagin causes effective cell growth inhibition, induces apoptosis and generates single-strand breaks in cancer cells. Incubation of cancer cells with scavengers of ROS and neocuproine inhibited the cytotoxic action of plumbagin proving that generation of ROS and Cu(I) are the critical mediators in plumbagin-induced cell growth inhibition. This study is the first to investigate the copper-mediated anticancer mechanism of plumbagin in human cancer cells and these properties of plumbagin could be further explored for the development of anticancer agents with higher therapeutic indices, especially for skin cancer.

  11. A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice.

    PubMed

    Park, Doori; Park, Chan-Won; Choi, YoungJin; Lin, Jingjing; Seo, Dong-Hyun; Kim, Han-Sung; Lee, Soo Young; Kang, In-Cheol

    2016-08-01

    Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin αvβ3-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay. IPS-02001 (6,7-Dichloro-2,3,5,8-tetrahydroxy-1,4-naphthoquinone) was screened from different compound libraries (InterBioScreen, Commercial libraries) using an in silico structure-based molecular docking simulation method and a protein chip-based protein-protein interaction assay system. Additionally, integrin αvβ3, an adhesion receptor expressed in osteoclasts (OCs), was implicated in the regulation of OC function via regulation of the cytoskeletal organization of OCs. IPS-02001 blocked OC maturation from murine bone marrow-derived macrophages, as well as the resorptive function of OCs. Moreover, treatment with IPS-02001 impaired downstream signaling of integrin αvβ3 linked to Pyk2, c-Src, PLCγ2, and Vav3 and disrupted the actin cytoskeleton in mature OCs. Furthermore, IPS-02001 blocked RANKL-induced bone destruction by reducing the number of OCs and protected against ovariectomy-induced bone loss in mice. Thus, IPS-02001 may represent a promising new class of anti-resorptive drugs for treatment of bone diseases associated with increased OC function. PMID:27187277

  12. Buparvaquone is active against Neospora caninum in vitro and in experimentally infected mice.

    PubMed

    Müller, Joachim; Aguado-Martinez, Adriana; Manser, Vera; Balmer, Vreni; Winzer, Pablo; Ritler, Dominic; Hostettler, Isabel; Arranz-Solís, David; Ortega-Mora, Luis; Hemphill, Andrew

    2015-04-01

    The naphthoquinone buparvaquone is currently the only drug used against theileriosis. Here, the effects of buparvaquone were investigated in vitro and in an experimental mouse model for Neospora caninum infection. In 4-day proliferation assays, buparvaquone efficiently inhibited N. caninum tachyzoite replication (IC50 = 4.9 nM; IC100 = 100 nM). However, in the long term tachyzoites adapted and resumed proliferation in the presence of 100 nM buparvaquone after 20 days of cultivation. Parasiticidal activity was noted after 9 days of culture in 0.5 µM or 6 days in 1 µM buparvaquone. TEM of N. caninum infected fibroblasts treated with 1 µM buparvaquone showed that the drug acted rather slowly, and ultrastructural changes were evident only after 3-5 days of treatment, including severe alterations in the parasite cytoplasm, changes in the composition of the parasitophorous vacuole matrix and a diminished integrity of the vacuole membrane. Treatment of N. caninum infected mice with buparvaquone (100 mg/kg) either by intraperitoneal injection or gavage prevented neosporosis symptoms in 4 out of 6 mice in the intraperitoneally treated group, and in 6 out of 7 mice in the group receiving oral treatment. In the corresponding controls, all 6 mice injected intraperitoneally with corn oil alone died of acute neosporosis, and 4 out of 6 mice died in the orally treated control group. Assessment of infection intensities in the treatment groups showed that, compared to the drug treated groups, the controls showed a significantly higher parasite load in the lungs while cerebral parasite load was higher in the buparvaquone-treated groups. Thus, although buparvaquone did not eliminate the parasites infecting the CNS, the drug represents an interesting lead with the potential to eliminate, or at least diminish, fetal infection during pregnancy. PMID:25941626

  13. Isolation and characterization of photosynthetic reaction centers from Rhodopseudomonas capsulata and Rhodopseudomonas sphaeroides

    SciTech Connect

    Worland, S.T.

    1984-09-01

    Reaction centers were isolated by affinity chromatography on equine cytochrome C. Peripheral proteins were removed with 0.05% LDAO. Absorption and EPR spectra and bleaching assays indicate that the reaction centers retained their electron donors and acceptors in the native environment. Three reaction center polypeptides were isolated and submitted for amino-terminal sequence determination. By comparing these sequences to those deduced from DNA, it was established that the M and L subunits are post-translationally modified to remove the aminoterminal Met, whereas the H subunit is not. Inhibition of O/sub 2/ evolution in photosystem II particles from spinach by naphthoquinone derivatives show O/sub 2/ inhibition by bromomethyl and acetoxymethyl derivatives but not with hydroxymethyl derivatives. Inhibition by acetoxymethyl derivatives in irreversible and dependent on illumination suggesting that reduction of the quinone is necessary. Therefore acetoxymethyl derivatives may be useful as suicide reagents for labelling quinone binding sites. Procedures were developed to extract one or both of the quinones present in reaction centers and preserve the integrity of the co-factor binding sites. The H and M subunits were cleaned using furmic acid. Both fragments were isolated from the H subunit, while the larger fragment was isolated from the M subunit. Electrophoretic mobilities of the isolated fragments agrees well with the expected molecular weights. The L subunit was digested with Staphylococcus areus vs protease. The pattern obtained was consistant with the potential sites of cleavage, but it was not possible to assign cleavage sites unambiguously. 112 references, 37 figures, 2 tables.

  14. Matrix-mediated canal formation in primmorphs from the sponge Suberites domuncula involves the expression of a CD36 receptor-ligand system.

    PubMed

    Müller, Werner E G; Thakur, Narsinh L; Ushijima, Hiroshi; Thakur, Archana N; Krasko, Anatoli; Le Pennec, Gaël; Indap, Madhavi M; Perovic-Ottstadt, Sanja; Schröder, Heinz C; Lang, Gerhard; Bringmann, Gerhard

    2004-05-15

    Sponges (Porifera), represent the phylogenetically oldest metazoan phylum still extant today. Recently, molecular biological studies provided compelling evidence that these animals share basic receptor/ligand systems, especially those involved in bodyplan formation and in immune recognition, with the higher metazoan phyla. An in vitro cell/organ-like culture system, the primmorphs, has been established that consists of proliferating and differentiating cells, but no canals of the aquiferous system. We show that after the transfer of primmorphs from the demosponge Suberites domuncula to a homologous matrix (galectin), canal-like structures are formed in these 3D-cell aggregates. In parallel with the formation of these structures a gene is expressed whose deduced protein falls into the CD36/LIMPII receptor family. The receptor was cloned and found to be strongly expressed after adhesion to the galectin matrix. This process was suppressed if primmorphs were co-incubated with a homologous polypeptide containing the CSVTCG domain, as found in thrombospondin-1 (and related) molecules of vertebrates. In situ hybridization studies revealed that the S. domuncula CD36/LIMPII receptor is localized in the pinacocytes that surround the canals of the sponge. Furthermore, a secondary metabolite from a sponge-associated bacterium was isolated and characterized, the 2-methylthio-1,4-naphthoquinone (MTN). MTN causes inhibition of cell proliferation of vertebrate tumor cells at concentrations of >80 ng/ml. However, doses of only 2 ng are required to potently inhibit angiogenesis in the chick chorio-allantoic membrane assay. At concentrations of 10 ng/ml this compound was also found to suppress the expression of the S. domuncula CD36/LIMPII; this result is a first indication that this secondary metabolite has a conserved functional activity: the suppression of the formation of the circulation system, from sponges to vertebrates.

  15. Phytochemical screening and anti-inflammatory activity of Cnidoscolus quercifolius (Euphorbiaceae) in mice

    PubMed Central

    de Araújo Gomes, Leandra Macedo; de Andrade, Thayne Mayra; Silva, Juliane Cabral; de Lima, Julianeli Tolentino; Quintans-Junior, Lucindo José; da Silva Almeida, Jackson Roberto Guedes

    2014-01-01

    Background: Cnidoscolus quercifolius is a species popularly known as favela and faveleira, and belonging to the Caatinga biome (semi-arid vegetation, Brazil), where is used in folk medicine as an anti-inflammatory. Objective: The aim was to evaluate the anti-inflammatory effect of the ethanolic extract from barks (Cqb-EtOH) and leaves (Cql-EtOH) of C. quercifolius in mice using experimental models of inflammation. Materials and Methods: The preliminary phytochemical analysis of the ethanolic extract was performed. The activity was evaluated by paw edema induced by carrageenan and leukocytes migration to the peritoneal cavity induced by carrageenan methods. Results: A preliminary analysis of Cqb-EtOH revealed that it contained coumarins, flavonoids, monoterpenes/diterpenes and naphthoquinones, while the Cql-EtOH showed positive reaction to coumarins, anthracene derivatives, flavonoids, lignans and triterpenes/steroids. Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited significantly (P < 0.01) the increase in the edema volume after administration of carrageenan. In the peritonitis test, acute pretreatment with Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited the leukocyte migration. Conclusions: It can be concluded that extracts from the barks and leaves of C. quercifolius have anti-inflammatory activity, which supports the popular use of this plant to treat inflammation. Thus, extracts has significant anti-inflammatory properties, which are related probably to inhibition of release of mediators of the inflammatory process. PMID:25276074

  16. Solvation numbers and hydration constant for thorium(IV) in ethanol-water medium

    SciTech Connect

    Sedaira, H.; Idriss, K.A.; Hashem, E.Y.

    1996-01-01

    The solvation number and hydration constant of Th{sup 4+} in ethanol-water medium were determined at 25{degrees}C using UV-spectral and electrochemical measurements. A solvate formation equilibrium is demonstrated and characterized. Three molecules of ethanol (S) can bond to the metal cation with strengths comparable to that for H{sub 2}O to form ThS{sub 3}(H{sub 2}O){sub 3}{sup 4+}. Formation of thorium monochelate with lawsone (2-hydroxy-1.4-naphthoquinone) eliminates bonding with alcohol molecules. The dissociation constant of the chelating agent {sub s}K{sub a} and the formation contant of the monochelated metal ion {sub s}K{sub f}{sup *} that are essentially independent of the solution composition are evaluated. Hydration titrations involving thorium-lawsone monochlate are performed and the data obtained from the changes of pH with solvent composition are analyzed. The solution independent constant, {sub s}K{sub f}{sup *} for thorium-lawsone complex formation in mixed aqueous ethanol is given by log {sub x}K{sub f}{sup *}=vpK{sub a} + log{sub s}K{sub h} - log [LH] - vpH + 3 log v where vpK{sub a} is the dissociation constant of the chelating agent LH in the solvent system of v volume fraction of water and {sub s}K{sub h} is the solution-independent hydration constant of thorium (IV) in the solvent system. Log-values for the constants {sub s}K{sub h}, {sub s}K{sub f}{sup *} and {sub s}K{sub z}{sup *} are found to be 7.8 {plus_minus}0.02, 11.38{plus_minus}0.04 and -0.753, respectively.

  17. Formation of environmentally persistent free radicals from the heterogeneous reaction of ozone and polycyclic aromatic compounds.

    PubMed

    Borrowman, Cuyler K; Zhou, Shouming; Burrow, Timothy E; Abbatt, Jonathan P D

    2016-01-01

    In the 1980s long-lived radical species were identified in cigarette tar. Since then, environmentally persistent free radicals (EPFRs) have been observed in ambient particulate matter, and have been generated in particulate matter generated from internal combustion engines. For the first time, we measure in situ the formation and decay of EPFRs through the heterogeneous reaction of ozone and several polycyclic aromatic compounds (PAC). Solid anthracene (ANT), pyrene (PY), benzo[a]pyrene (BAP), benzo[ghi]perylene (BGHIP), 1,4-naphthoquinone (1,4NQ), and 9,10-anthraquinone (AQ) were reacted with gas-phase ozone in a flow system placed in the active cavity of an electron paramagnetic resonance (EPR) spectrometer, and the formation of radicals was measured on the timescale of tens of minutes at ambient levels of ozone down to 30 ppb. For most substrates the net radical production is initially rapid, slows at intermediate times, and is followed by a slow decay. For oxidized solid BAP, radical signal persists for many days in the absence of ozone. To evaluate the effect of substrate phase, the solid PAHs were also dissolved in squalane, an organic oil inert to ozone, which yielded a much higher maximum radical concentration and faster radical decay when exposed to ozone. With higher mobility, reactants were apparently able to more easily diffuse and react with each other, yielding the higher radical concentrations. The EPR spectra exhibit three radicals types, two of which have been assigned to semiquinone species and one to a PAH-derived, carbon-centered radical. Although our system uses levels of PAC not typically found in the environment it is worth noting that the amounts of radical formed, on the order of 10(18) radicals per g, are comparable to those observed in ambient particulate matter. PMID:26603953

  18. Potential of herbs in skin protection from ultraviolet radiation

    PubMed Central

    Korać, Radava R.; Khambholja, Kapil M.

    2011-01-01

    Herbs have been used in medicines and cosmetics from centuries. Their potential to treat different skin diseases, to adorn and improve the skin appearance is well-known. As ultraviolet (UV) radiation can cause sunburns, wrinkles, lower immunity against infections, premature aging, and cancer, there is permanent need for protection from UV radiation and prevention from their side effects. Herbs and herbal preparations have a high potential due to their antioxidant activity, primarily. Antioxidants such as vitamins (vitamin C, vitamin E), flavonoids, and phenolic acids play the main role in fighting against free radical species that are the main cause of numerous negative skin changes. Although isolated plant compounds have a high potential in protection of the skin, whole herbs extracts showed better potential due to their complex composition. Many studies showed that green and black tea (polyphenols) ameliorate adverse skin reactions following UV exposure. The gel from aloe is believed to stimulate skin and assist in new cell growth. Spectrophotometer testing indicates that as a concentrated extract of Krameria triandra it absorbs 25 to 30% of the amount of UV radiation typically absorbed by octyl methoxycinnamate. Sesame oil resists 30% of UV rays, while coconut, peanut, olive, and cottonseed oils block out about 20%. A “sclerojuglonic” compound which is forming from naphthoquinone and keratin is the reaction product that provides UV protection. Traditional use of plant in medication or beautification is the basis for researches and making new trends in cosmetics. This review covers all essential aspects of potential of herbs as radioprotective agents and its future prospects. PMID:22279374

  19. Analysis of polycyclic aromatic hydrocarbons and their oxygen-containing derivatives and metabolites in soils.

    PubMed

    Bandowe, Benjamin A Musa; Wilcke, Wolfgang

    2010-01-01

    Although polycyclic aromatic hydrocarbons (PAHs) have been extensively studied, the knowledge of their oxygen-containing derivatives and metabolites (OPAHs) in soils is limited. We modified and tested an existing analytical protocol involving pressurized liquid extraction of soil followed by fractionation of target compounds into PAHs and OPAHs on a silica gel column and gas chromatography/ mass spectrometry-based separation and quantification. Polycyclic aromatic hydrocarbons and carbonyl-OPAHs were quantified directly after separation on silica gel columns, and hydroxyl/carboxyl-OPAHs were quantified after silylation with N,O-bis(trimethylsilyl)trifluoroacetamide. Recoveries between 78 and 97% (relative standard deviation [RSD], 5-12%) were obtained for six carbonyl-OPAHs, whereas 1,2-acenaphthenequinone and 1,4-naphthoquinone showed lower recoveries of 34 and 44% (RSD, 19 and 28%, respectively). Five hydroxyl/carboxyl-OPAHs had recoveries between 36 and 70% (RSD, 13-46%), six others had between 2 and 7% (RSD, 8-25%), and nine were lost in sample preparation. Limits of detection ranged from 0.1 to 1.6 ng g(-1) for OPAHs and from 0.01 to 0.56 ng g(-1) for PAHs. The protocol was applied to soils from a former gasworks site, Berlin, an urban soil from Mainz, both in Germany, and a forest soil from near Manaus, Brazil. The sums of 34 PAH concentrations were 107,000, 3505, and 21 ng g(-1); those of seven carbonyl-OPAHs were 15,690, 170, and 7 ng g(-1); and those of 11 hydroxyl/carboxyl-OPAHs 518, 36, and 16 ng g(-1) for Berlin, Mainz, and Manaus soils, respectively. Several OPAHs were present at concentrations higher than or equal to their parent PAHs, demonstrating the importance of OPAH measurement for the assessment of PAH-related environmental risks. PMID:20830923

  20. Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress.

    PubMed

    Schneider, Lonnie; Giordano, Samantha; Zelickson, Blake R; S Johnson, Michelle; A Benavides, Gloria; Ouyang, Xiaosen; Fineberg, Naomi; Darley-Usmar, Victor M; Zhang, Jianhua

    2011-12-01

    Cell differentiation is associated with changes in metabolism and function. Understanding these changes during differentiation is important in the context of stem cell research, cancer, and neurodegenerative diseases. An early event in neurodegenerative diseases is the alteration of mitochondrial function and increased oxidative stress. Studies using both undifferentiated and differentiated SH-SY5Y neuroblastoma cells have shown distinct responses to cellular stressors; however, the mechanisms remain unclear. We hypothesized that because the regulation of glycolysis and oxidative phosphorylation is modulated during cellular differentiation, this would change bioenergetic function and the response to oxidative stress. To test this, we used retinoic acid (RA) to induce differentiation of SH-SY5Y cells and assessed changes in cellular bioenergetics using extracellular flux analysis. After exposure to RA, the SH-SY5Y cells had an increased mitochondrial membrane potential, without changing mitochondrial number. Differentiated cells exhibited greater stimulation of mitochondrial respiration with uncoupling and an increased bioenergetic reserve capacity. The increased reserve capacity in the differentiated cells was suppressed by the inhibitor of glycolysis 2-deoxy-d-glucose. Furthermore, we found that differentiated cells were substantially more resistant to cytotoxicity and mitochondrial dysfunction induced by the reactive lipid species 4-hydroxynonenal or the reactive oxygen species generator 2,3-dimethoxy-1,4-naphthoquinone. We then analyzed the levels of selected mitochondrial proteins and found an increase in complex IV subunits, which we propose contributes to the increase in reserve capacity in the differentiated cells. Furthermore, we found an increase in MnSOD that could, at least in part, account for the increased resistance to oxidative stress. Our findings suggest that profound changes in mitochondrial metabolism and antioxidant defenses occur upon

  1. Plumbagin Suppresses the Invasion of HER2-Overexpressing Breast Cancer Cells through Inhibition of IKKα-Mediated NF-κB Activation

    PubMed Central

    Kawiak, Anna; Domachowska, Anna

    2016-01-01

    HER2-overexpressing breast cancers account for about 30% of breast cancer occurrences and have been correlated with increased tumor aggressiveness and invasiveness. The nuclear factor-κB (NF-κB) is overexpressed in a subset of HER2-positive breast cancers and its upregulation has been associated with the metastatic potential of HER2-overexpressing tumors. The present study aimed at determining the potential of plumbagin, a naturally occurring naphthoquinone, to inhibit the invasion of HER2-overexpressing breast cancer cells and determine the involvement of NF-κB inhibition in plumbagin-mediated cell invasion suppression. In the present research we showed that plumbagin inhibited the transcriptional activity of NF-κB in HER2-positive breast cancer cells. The suppression of NF-κB activation corresponded with the inhibition of NF-κB p65 phosphorylation and downregulation of NF-κB-regulated matrix metalloproteinase 9 (MMP-9) expression. Plumbagin suppressed the invasion of HER2-overexpressing breast cancer cells and the inhibition of cell invasion was associated with the ability of plumbagin to inhibit NF-κB transcriptional activity. The silencing of NF-κB p65 increased the sensitivity of HER2-overexpressing breast cancer cells to plumbagin-induced cell invasion inhibition. NF-κB inhibition was associated with IκB kinase α (IKKα) activity suppression and inhibition of IκBα phosphorylation and degradation. The knockdown of IKKα resulted in increased sensitivity of HER2-positive cells to plumbagin-induced suppression of NF-κB transcriptional activity and expression of MMP-9. In conclusion, plumbagin inhibits the invasion of HER2-overexpressing breast cancer cells through the inhibition of IKKα-mediated NF-κB activation and downregulation of NF-κB-regulated MMP-9 expression. PMID:27727280

  2. Protective, antioxidative and antiapoptotic effects of 2-methoxy-6-acetyl-7-methyljuglone from Polygonum cuspidatum in PC12 cells.

    PubMed

    Li, Ying Bo; Lin, Zhu Qing; Zhang, Zai Jun; Wang, Mei Wei; Zhang, Huan; Zhang, Qing Wen; Lee, Simon Ming Yuen; Wang, Yi Tao; Hoi, Pui Man

    2011-03-01

    Much correlative evidence indicates that the oxidative modification of protein by reactive oxygen species (ROS) is involved in normal aging as well as the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. In this study, we explored the antioxidative and neuroprotective effects of a naphthoquinone, 2-methoxy-6-acetyl-7-methyljuglone (MAM), purified from the dried rhizome of POLYGONUM CUSPIDATUM (Chinese name Hu-Zhang). Pretreatments with MAM (24 h) were investigated for their protective effects against apoptosis induced by the oxidizing agent TERT-butyl hydroperoxide ( T-BHP) in PC12 cells. The results indicated that MAM pretreatments could effectively protect PC12 cells against cytotoxicity induced by T-BHP in a dose-dependent manner. Cell viability was determined by both MTT and LDH assays. Increasing concentrations of MAM enhanced cell viability significantly and completely prevented cell death induced by T-BHP at 2.5 µM. The corresponding extracellular lactate dehydrogenase (LDH) levels were also attenuated significantly by various concentrations of MAM. In addition, it was found that the antioxidative effect of MAM was stronger than those of resveratrol and lipoic acid. The antiapoptotic property of MAM was further investigated with Hoechst 33342 nuclear staining and TUNEL assay. Pretreatments of MAM were able to prevent the T-BHP-induced nucleus fragmentation and accumulation of apoptotic bodies (commonly accepted as markers of apoptosis) inside the cells in a dose-dependent manner. T-BHP induced the phosphorylation of ERK 1/2, JNK and p38 MAPK, which were all impeded by pretreatments with MAM, indicating that MAM may act as a potent antioxidant which significantly interferes with the MAPK apoptotic cascades, probably rescuing cells by inhibiting the death pathways. PMID:20922651

  3. Assessing the oxidative potential of isoprene-derived epoxides and secondary organic aerosol

    NASA Astrophysics Data System (ADS)

    Kramer, Amanda J.; Rattanavaraha, Weruka; Zhang, Zhenfa; Gold, Avram; Surratt, Jason D.; Lin, Ying-Hsuan

    2016-04-01

    Fine particulate matter (PM2.5) is known to contribute to adverse health effects, such as asthma, cardiopulmonary disease, and lung cancer. Secondary organic aerosol (SOA) is a major component of PM2.5 and can be enhanced by atmospheric oxidation of biogenic volatile organic compounds in the presence of anthropogenic pollutants, such as nitrogen oxides (NOx) and sulfur dioxide. However, whether biogenic SOA contributes to adverse health effects remains unclear. The objective of this study was to assess the potential of isoprene-derived epoxides and SOA for generating reactive oxygen species (ROS) in light of the recent recognition that atmospheric oxidation of isoprene in the presence of acidic sulfate aerosol is a major contributor to the global SOA burden. The dithiothreitol (DTT) assay was used to characterize the ROS generation by the isoprene-derived epoxides, trans-β-isoprene epoxydiol (trans-β-IEPOX) and methacrylic acid epoxide (MAE), and their hydrolysis products, the 2-methyltetrol diastereomers (2-MT), 2-methylglyceric acid (2-MG), their organosulfate derivatives, as well as an isoprene-derived hydroxyhydroperoxide (ISOPOOH). In addition, ROS generation potential was evaluated for total SOA produced from photooxidation of isoprene and methacrolein (MACR) as well as from the reactive uptake of trans-β-IEPOX and MAE onto acidified sulfate aerosol. The high-NOx regime, which yields 2-MG-, MAE- and MACR-derived SOA has a higher ROS generation potential than the low-NOx regime, which yields 2-MT, IEPOX- and isoprene-derived SOA. ISOPOOH has an ROS generation potential similar to 1,4-naphthoquinone (1,4-NQ), suggesting a significant contribution of aerosol-phase organic peroxides to PM oxidative potential. MAE- and MACR-derived SOA show equal or greater ROS generation potential than reported in studies on diesel exhaust PM, highlighting the importance of a comprehensive investigation of the toxicity of isoprene-derived SOA.

  4. Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling

    PubMed Central

    Xue, Yuan-Liang; Meng, Xiang-Qi; Ma, Long-Jun; Yuan, Zhen

    2016-01-01

    Plumbagin, a naphthoquinone constituent of Plumbago zeylanica L. (Plumbaginaceae) is widely used in traditional Chinese medicine as an antifungal, antibacterial and anti-inflammatory agent. Plumbagin is known to exhibit proapoptotic, antiangiogenic and antimetastatic effects in cancer cells. The transcriptional co-factor four and a half LIM domains 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of gene expression, signal transduction and cell proliferation and differentiation, and also acts as a tumor suppressor or oncoprotein depending on the tissue microenvironment. The present study investigated the effect of plumbagin on FHL2 expression, Wnt/β-catenin signalling and its anti-proliferative activity in various human osteosarcoma cell lines, including SaOS2, MG63, HOS and U2OS. The cells were exposed to plumbagin and the expression of FHL2 was evaluated using western blot analysis. Furthermore, the anti-proliferative effect of plumbagin was evaluated using a 3-(4,5 dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, since FHL2 is involved in Wnt/β-catenin signaling, the effect of plumbagin on β-catenin and its primary target genes, including v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) and WNT1 inducible signaling pathway protein-1 (WISP-1), was evaluated using western blot analysis. It was observed that plumbagin suppressed the expression of FHL2 and exhibited significant anti-proliferative activity in osteosarcoma cells. It also attenuated Wnt/β-catenin signalling by downregulating β-catenin and its target genes, including c-Myc and WISP-1. In conclusion, plumbagin demonstrated anti-proliferative activity in osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling. PMID:27446400

  5. An adjustment factor for mode-of-action uncertainty with dual-mode carcinogens: the case of naphthalene-induced nasal tumors in rats.

    PubMed

    Bogen, Kenneth T

    2008-08-01

    The U.S. Environmental Protection Agency (USEPA) guidelines for cancer risk assessment recognize that some chemical carcinogens may have a site-specific mode of action (MOA) involving mutation and cell-killing-induced hyperplasia. The guidelines recommend that for such dual MOA (DMOA) carcinogens, judgment should be used to compare and assess results using separate "linear" (genotoxic) versus "nonlinear" (nongenotoxic) approaches to low-level risk extrapolation. Because the guidelines allow this only when evidence supports reliable risk extrapolation using a validated mechanistic model, they effectively prevent addressing MOA uncertainty when data do not fully validate such a model but otherwise clearly support a DMOA. An adjustment-factor approach is proposed to address this gap, analogous to reference-dose procedures used for classic toxicity endpoints. By this method, even when a "nonlinear" toxicokinetic model cannot be fully validated, the effect of DMOA uncertainty on low-dose risk can be addressed. Application of the proposed approach was illustrated for the case of risk extrapolation from bioassay data on rat nasal tumors induced by chronic lifetime exposure to naphthalene. Bioassay data, toxicokinetic data, and pharmacokinetic analyses were determined to indicate that naphthalene is almost certainly a DMOA carcinogen. Plausibility bounds on rat-tumor-type-specific DMOA-related uncertainty were obtained using a mechanistic two-stage cancer risk model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Bound-specific adjustment factors were then used to reduce naphthalene risk estimated by linear extrapolation (under the default genotoxic MOA assumption), to account for the DMOA exhibited by this compound. PMID:18564993

  6. Kinetic phases in the electron transfer from P+QA-QB to P+QAQB- and the associated processes in Rhodobacter sphaeroides R-26 reaction centers.

    PubMed

    Li, J; Gilroy, D; Tiede, D M; Gunner, M R

    1998-03-01

    Electron transfer from P+QA-QB to form P+QAQB- was measured in Rhodobacter sphaeroides R-26 reaction centers (RCs) where the native primary quinone, ubiquinone-10 (UQA), was replaced by 2-methyl-3-phytyl-1,4-naphthoquinone (MQA). The native secondary quinone, UQ-10, was retained as UQB. The difference spectrum of the semiquinone MQA- minus UQB- absorption is very similar to that of MQ- minus UQ- in solution (398-480 nm). Thus, the absorption change provides a direct monitor of the electron transfer from MQA- to UQB. In contrast, when both QA and QB are UQ-10 the spectral difference between UQA- and UQB- arises from electrochromic responses of RC chromophores. Three kinetic processes are seen in the near UV (390-480 nm) and near-IR (740-820 nm). Analysis of the time-correlated spectra support the conclusion that the changes at tau1 approximately 3 micros are mostly due to electron transfer, electron transfer and charge compensation are mixed in tau2 approximately 80 micros, while little or no electron transfer occurs at 200-600 micros (tau3) in MQAUQB RCs. The 80-micros rate has been previously observed, while the fast component has not. The fast phase represents 60% of the electron-transfer reaction (398 nm). The activation energy for electron transfer is DeltaG approximately 3.5 kcal/mol for both tau1 and tau2 between 0 and 30 degrees C. In isolated RCs with UQA, if there is any fast component, it appears to be faster and less important than in the MQA reconstituted RCs.

  7. Secondary Metabolites from Plants Inhibiting ABC Transporters and Reversing Resistance of Cancer Cells and Microbes to Cytotoxic and Antimicrobial Agents

    PubMed Central

    Wink, Michael; Ashour, Mohamed L.; El-Readi, Mahmoud Zaki

    2012-01-01

    Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion. PMID:22536197

  8. Molecular structures and antiproliferative activity of side-chain saturated and homologated analogs of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone

    NASA Astrophysics Data System (ADS)

    Pal, Sanjima; Jadhav, Mahesh; Weyhermüller, Thomas; Patil, Yogesh; Nethaji, M.; Kasabe, Umesh; Kathawate, Laxmi; Konkimalla, V. Badireenath; Salunke-Gawali, Sunita

    2013-10-01

    Side chain homologated derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: pentyl; L-5, hexyl; L-6, heptyl; L-7 and octyl; L-8} have been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-visible spectroscopy and LC-MS. Compounds, L-4, {n-alkyl: butyl; L-4}, L-6 and L-8 have been characterized by single crystal X-ray diffraction studies. The single crystal X-ray structures reveal that L-4 and L-8 crystallizes in P21 space group, while L-6 in P21/c space group. Molecules of L-4 and L-8 from polymeric chains through Csbnd H⋯O and Nsbnd H⋯O close contacts. L-6 is a dimer formed by Nsbnd H⋯O interaction. Slipped π-π stacking interactions are observed between quinonoid and benzenoid rings of L-4 and L-8. Orientations of alkyl group in L-4 and L-8 is on same side of the chain and polymeric chains run opposite to one another to form zip like structure to the alkyl groups. Antiproliferative activities of L-1 to L-8{n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} were studied in cancer cells of colon (COLO205), brain (U87MG) and pancreas (MIAPaCa2) where L-1, L-2 and L-3 were active in MIAPaCa2 (L-1 = L-2 > L-3) and COLO205 (L-2 = L-3 > L-1) and inactive in U87MG. From antiproliferative studies with compounds L-1 to L-8 it can be concluded that homologation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone with saturated methyl groups yielded tissue specific compounds such as L-2 (for MIAPaCa2) and L-3 (for COLO205) with optimal activity.

  9. Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plants.

    PubMed

    González-Coloma, Azucena; Reina, Matías; Sáenz, Claudia; Lacret, Rodney; Ruiz-Mesia, Lastenia; Arán, Vicente J; Sanz, Jesús; Martínez-Díaz, Rafael A

    2012-04-01

    Extracts (34) from eight plant species of the Peruvian Amazonia currently used in traditional Peruvian medicine, mostly as antileishmanial remedies and also as painkiller, antiseptic, antipyretic, anti-inflamatory, antiflu, astringent, diuretic, antipoison, anticancerous, antiparasitic, insecticidal, or healing agents, have been tested for their antileishmanial, antitrypanosomal, and cytotoxic activity. Plant species were selected based on interviews conducted with residents of rural areas. The different plant parts were dried, powdered, and extracted by maceration with different solvents (hexane, chloroform, and 70% ethanol-water). These extracts were tested on promastigote forms of Leishmania infantum strain PB75, epimastigote forms of Trypanosoma cruzi strain Y, and the mammalian CHO cell line. Parasite viability and nonspecific cytotoxicity were analyzed by a modified MTT colorimetric assay method. The isolation and identification of pure compounds from selected extracts were performed by column chromatography, gas chromatography mass spectrometry (GC-MS; mixtures), spectroscopic techniques [MS, infrared (IR), ultraviolet (UV)], and mono and two-dimensional (1)H and (13)C nuclear magnetic resonance (NMR; COSY, HSQC, NOESY) experiments. Chondodendron tomentosum bark and Cedrela odorata were the most active extracts against Leishmania, while C. odorata and Aristoloquia pilosa were the most active against Trypanosoma, followed by Tabebuia serratifolia, Tradescantia zebrina, and Zamia ulei. Six compounds and two mixtures were isolated from Z. ulei [cycasin (1)], T. serratifolia {mixtures 1-2, and naphthoquinones 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (2) and 2-(1-hydroxyethyl)-4H,9H-naphtho[2,3-b]furan-4,9-dione (3)}, and C. tomentosum [chondrocurine (4); (S,S')-12-O-methyl(+)-curine (5); and cycleanine (6)]. Four compounds and the two mixtures exhibited significant activity.

  10. Shikonin Exerts Antitumor Activity via Proteasome Inhibition and Cell Death Induction in vitro and in vivo

    PubMed Central

    Yang, Huanjie; Zhou, Ping; Huang, Hongbiao; Chen, Di; Ma, Ningfang; Cui, Cindy Qiuzhi; Shen, Shouxing; Dong, Weihua; Zhang, Xiaoyan; Lian, Wen; Wang, Xuejun; Dou, Q. Ping; Liu, Jinbao

    2009-01-01

    Dysregulation of the ubiquitin-proteasome pathway plays an essential role in tumor growth and development. Shikonin, a natural naphthoquinone isolated from the traditional Chinese medicine Zi Cao (gromwell), has been reported to possess tumor cell-killing activity, and results from a clinical study using a shikonin-containing mixture demonstrated its safety and efficacy for the treatment of late-stage lung cancer. In the present study, we reported that shikonin is an inhibitor of tumor proteasome activity in vitro and in vivo. Our computational modeling predicts that the carbonyl carbons C1 and C4 of shikonin potentially interact with the catalytic site of β5 chymotryptic subunit of the proteasome. Indeed, shikonin potently inhibits the chymotrypsin-like activity of purified 20S proteasome (IC50 12.5 μmol/L) and tumor cellular 26S proteasome (IC50 between 2-16 μmol/L). Inhibition of the proteasome by shikonin in murine hepatoma H22, leukemia P388 and human prostate cancer PC-3 cultures resulted in accumulation of ubiquitinated proteins and several proteasome target proapoptotic proteins (IκB-α, Bax and p27), followed by induction of cell death. Shikonin treatment resulted in tumor growth inhibition in both H22 allografts and PC-3 xenografts, associated with suppression of the proteasomal activity and induction of cell death in vivo. Finally, shikonin treatment significantly prolonged the survival period of mice bearing P388 leukemia. Our results indicate that the tumor proteasome is one of the cellular targets of shikonin, and inhibition of the proteasome activity by shikonin contributes to its anti-tumor property. PMID:19165859

  11. Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species.

    PubMed

    Oja, Terhi; San Martin Galindo, Paola; Taguchi, Takaaki; Manner, Suvi; Vuorela, Pia M; Ichinose, Koji; Metsä-Ketelä, Mikko; Fallarero, Adyary

    2015-10-01

    Streptomyces bacteria are renowned for their ability to produce bioactive secondary metabolites. Recently, synthetic biology has enabled the production of intermediates and shunt products, which may have altered biological activities compared to the end products of the pathways. Here, we have evaluated the potential of recently isolated alnumycins and other closely related pyranonaphthoquinone (PNQ) polyketides against Staphylococcus aureus biofilms. The antimicrobial potency of the compounds against planktonic cells and biofilms was determined by redox dye-based viability staining, and the antibiofilm efficacy of the compounds was confirmed by viable counting. A novel antistaphylococcal polyketide, alnumycin D, was identified. Unexpectedly, the C-ribosylated pathway shunt product alnumycin D was more active against planktonic and biofilm cells than the pathway end product alnumycin A, where a ribose unit has been converted into a dioxane moiety. The evaluation of the antibiofilm potential of other alnumycins revealed that the presence of the ribose moiety in pyranose form is essential for high activity against preformed biofilms. Furthermore, the antibiofilm potential of other closely related PNQ polyketides was examined. Based on their previously reported activity against planktonic S. aureus cells, granaticin B, kalafungin, and medermycin were also selected for testing, and among them, granaticin B was found to be the most potent against preformed biofilms. The most active antibiofilm PNQs, alnumycin D and granaticin B, share several structural features that may be important for their antibiofilm activity. They are uncharged, glycosylated, and also contain a similar oxygenation pattern of the lateral naphthoquinone ring. These findings highlight the potential of antibiotic biosynthetic pathways as a source of effective antibiofilm compounds. PMID:26195520

  12. Induction of apoptosis by plumbagin through reactive oxygen species-mediated inhibition of topoisomerase II

    SciTech Connect

    Kawiak, Anna; Piosik, Jacek; Stasilojc, Grzegorz; Gwizdek-Wisniewska, Anna; Marczak, Lukasz; Stobiecki, Maciej; Lojkowska, Ewa

    2007-09-15

    Reactive oxygen species (ROS) have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis. Plumbagin, a naphthoquinone exhibiting antitumor activity, is known to generate ROS and has been found to inhibit the activity of topoisomerase II (Topo II) through the stabilization of the Topo II-DNA cleavable complex. The objective of this research was to clarify the role of ROS and Topo II inhibition in the induction of apoptosis mediated by plumbagin. As determined by the comet assay, plumbagin induced DNA cleavage in HL-60 cells, whereas in a cell line with reduced Topo II activity-HL-60/MX2, the level of DNA damage was significantly decreased. The onset of DNA strand break formation in HL-60 cells was delayed in comparison with the generation of intracellular ROS. In HL-60/MX2 cells, ROS were generated at a similar rate, whereas a significant reduction in the level of DNA damage was detected. The pretreatment of cells with N-acetylcysteine (NAC) attenuated plumbagin-induced DNA damage, pointing out to the involvement of ROS generation in cleavable complex formation. These results suggest that plumbagin-induced ROS does not directly damage DNA but requires the involvement of Topo II. Furthermore, experiments carried out using light spectroscopy indicated no direct interactions between plumbagin and DNA. The induction of apoptosis was significantly delayed in HL-60/MX2 cells indicating the involvement of Topo II inhibition in plumbagin-mediated apoptosis. Thus, these findings strongly suggest ROS-mediated inhibition of Topo II as an important mechanism contributing to the apoptosis-inducing properties of plumbagin.

  13. Round robin investigation of organic compounds in aqueous leachates of solid wastes: application to H-coal filter cake leachates

    SciTech Connect

    Avery, M.; Hilpert, L.; Jackson, L.; Junk, G.; Maskarinec, M.; Paule, R.C.; Raphaelian, L.; Richard, J.; White, C.M.

    1985-01-01

    The work presented in this report details efforts of six laboratories to develop methods for the analysis of aqueous leachates from fossil fuel solid wastes and to determine their accuracy and precision. Quantitative data on the concentrations of seventeen target organic compounds in aqueous leachates of a fossil fuel waste are presented. Many of the target analytes were selected from Appendices VII and VIII, of the May 19th, 1980, Federal Register. Some organic compounds that are not present in Appendices VII and VIII were also selected because of the probability of their presence in fossil fuel products, by-products, and wastes. These target analytes and four standard compounds that were used as internal standards are the following: Benz(a)anthracene, o-Cresol, Phenanthrene, Carbazole, Naphthalene, 1,4-Naphthoquinone, Phenol, 2-Fluorophenol (standard), n-Octacosane (standard), Azulene (standard), 2,3,4,5-Tetrachlorobiphenyl (standard), n-Tetradecane, 2-Naphthol, n-Hexanoic acid, Dibenzothiophene, Quinoline, Acenaphthylene, 1-Naphthylamine, 2-Picoline, 4-Aminobiphenyl, and Fluoranthene. An analytical method for the determination of organic compounds in aqueous leachates has been developed. This method was evaluated using a series of samples of increasing complexity, starting with simple synthetic aqueous leachates and ending with leachates of fossil fuel wastes. The present report describes the analytical results from four laboratories applying the previously developed analytical method to leachates of an H-Coal filter cake material. These leachates were obtained using both the standard ASTM Method D3987 and the EP leaching procedures. Ten additional compounds of interest were identified in the extract: Indan, Tetralin, 2-Methylnaphthalene, 1-Methylnaphthalene, Tetrahydroacenaphthene, Biphenyl, Acenaphthene, Dibenzofuran, Fluorene, and Diphenyl Ether. 11 references, 2 figures, 16 tables.

  14. Tumour-promoting activity of polycyclic aromatic hydrocarbons and their oxygenated or nitrated derivatives.

    PubMed

    Misaki, Kentaro; Takamura-Enya, Takeji; Ogawa, Hideoki; Takamori, Kenji; Yanagida, Mitsuaki

    2016-03-01

    Various types of polycyclic aromatic compounds (PACs) in diesel exhaust particles are thought to contribute to carcinogenesis in mammals. Although the carcinogenicity, mutagenicity and tumour-initiating activity of these compounds have been evaluated, their tumour-promoting activity is unclear. In the present study, to determine the tumour-inducing activity of PACs, including previously known mutagenic compounds in atmospheric environments, a transformation assay for promoting activity mediated by the release of contact inhibition was conducted for six polycyclic aromatic hydrocarbons (PAHs), seven oxygenated PAHs (oxy-PAHs) and seven nitrated PAHs (nitro-PAHs) using mouse embryonic fibroblast cells transfected with the v-Ha-ras gene (Bhas 42 cells). Of these, two PAHs [benzo[k]fluoranthene (B[k]FA) and benzo[b]fluoranthene (B[b]FA)], one oxy-PAH [6H-benzo[cd]pyren-6-one (BPO)] and two nitro-PAHs (3-nitro-7H-benz[de]anthracen-7-one and 6-nitrochrysene) were found to exhibit particularly powerful tumour-promoting activity (≥10 foci following exposure to <100nM). In addition, clear mRNA expression of CYP1A1, which is associated with aryl hydrocarbon receptor (AhR)-mediated activation, was observed following the exposure of cells to two PAHs (B[k]FA and B[b]FA) and three oxy-PAHs (1,2-naphthoquinone, 11H-benzo[b]fluoren-11-one and BPO). Further, an HO-1 antioxidant response activation was observed following exposure to B[k]FA, B[b]FA and BPO, suggesting that the induction of tumour-promoting activity in these compounds is correlated with the dysfunction of signal transduction via AhR-mediated responses and/or oxidative stress responses.

  15. Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy.

    PubMed

    Zalutsky, M R; Vaidyanathan, G

    2000-09-01

    Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of alpha-particles such as the heavy halogen astatine-211 (211At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include [211At]astatide, 211At- labeled particulates, 211At-labeled naphthoquinone derivatives, 211At-labeled methylene blue, 211At-labeled DNA precursors, meta-[211At]astatobenzylguanidine, 211At-labeled biotin conjugates, 211At-labeled bisphosphonates, and 211At-labeled antibodies and antibody fragments. The status of these 211At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211At-labeled targeted therapeutic, 211At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

  16. Kinetics of naphthalene metabolism in target and non-target tissues of rodents and in nasal and airway microsomes from the Rhesus monkey

    SciTech Connect

    Buckpitt, Alan; Morin, Dexter; Murphy, Shannon; Edwards, Patricia; Van Winkle, Laura

    2013-07-15

    Naphthalene produces species and cell selective injury to respiratory tract epithelial cells of rodents. In these studies we determined the apparent K{sub m}, V{sub max}, and catalytic efficiency (V{sub max}/K{sub m}) for naphthalene metabolism in microsomal preparations from subcompartments of the respiratory tract of rodents and non-human primates. In tissues with high substrate turnover, major metabolites were derived directly from naphthalene oxide with smaller amounts from conjugates of diol epoxide, diepoxide, and 1,2- and 1,4-naphthoquinones. In some tissues, different enzymes with dissimilar K{sub m} and V{sub max} appeared to metabolize naphthalene. The rank order of V{sub max} (rat olfactory epithelium > mouse olfactory epithelium > murine airways ≫ rat airways) correlated well with tissue susceptibility to naphthalene. The V{sub max} in monkey alveolar subcompartment was 2% that in rat nasal olfactory epithelium. Rates of metabolism in nasal compartments of the monkey were low. The catalytic efficiencies of microsomes from known susceptible tissues/subcompartments are 10 and 250 fold higher than in rat airway and monkey alveolar subcompartments, respectively. Although the strong correlations between catalytic efficiencies and tissue susceptibility suggest that non-human primate tissues are unlikely to generate metabolites at a rate sufficient to produce cellular injury, other studies showing high levels of formation of protein adducts support the need for additional studies. - Highlights: • Naphthalene is metabolized with high catalytic efficiency in susceptible tissue. • Naphthalene is metabolized at low catalytic efficiency in non-susceptible tissue. • Respiratory tissues of the non human primate metabolize naphthalene slowly.

  17. Buparvaquone is active against Neospora caninum in vitro and in experimentally infected mice

    PubMed Central

    Müller, Joachim; Aguado-Martinez, Adriana; Manser, Vera; Balmer, Vreni; Winzer, Pablo; Ritler, Dominic; Hostettler, Isabel; Arranz-Solís, David; Ortega-Mora, Luis; Hemphill, Andrew

    2015-01-01

    The naphthoquinone buparvaquone is currently the only drug used against theileriosis. Here, the effects of buparvaquone were investigated in vitro and in an experimental mouse model for Neospora caninum infection. In 4-day proliferation assays, buparvaquone efficiently inhibited N. caninum tachyzoite replication (IC50 = 4.9 nM; IC100 = 100 nM). However, in the long term tachyzoites adapted and resumed proliferation in the presence of 100 nM buparvaquone after 20 days of cultivation. Parasiticidal activity was noted after 9 days of culture in 0.5 µM or 6 days in 1 µM buparvaquone. TEM of N. caninum infected fibroblasts treated with 1 µM buparvaquone showed that the drug acted rather slowly, and ultrastructural changes were evident only after 3–5 days of treatment, including severe alterations in the parasite cytoplasm, changes in the composition of the parasitophorous vacuole matrix and a diminished integrity of the vacuole membrane. Treatment of N. caninum infected mice with buparvaquone (100 mg/kg) either by intraperitoneal injection or gavage prevented neosporosis symptoms in 4 out of 6 mice in the intraperitoneally treated group, and in 6 out of 7 mice in the group receiving oral treatment. In the corresponding controls, all 6 mice injected intraperitoneally with corn oil alone died of acute neosporosis, and 4 out of 6 mice died in the orally treated control group. Assessment of infection intensities in the treatment groups showed that, compared to the drug treated groups, the controls showed a significantly higher parasite load in the lungs while cerebral parasite load was higher in the buparvaquone-treated groups. Thus, although buparvaquone did not eliminate the parasites infecting the CNS, the drug represents an interesting lead with the potential to eliminate, or at least diminish, fetal infection during pregnancy. PMID:25941626

  18. Decolorization of azo dyes by Geobacter metallireducens.

    PubMed

    Liu, Guangfei; Zhou, Jiti; Chen, Congcong; Wang, Jing; Jin, Ruofei; Lv, Hong

    2013-09-01

    Geobacter metallireducens was found to be capable of decolorizing several azo dyes with different structures to various extents. Pyruvate, ethanol, acetate, propionate, and benzoate could support 66.3 ± 2.6-93.7 ± 2.1 % decolorization of 0.1 mM acid red 27 (AR27) in 40 h. The dependence of the specific decolorization rate on AR27 concentration (25 to 800 μM) followed Michaelis-Menten kinetics (K m = 186.9 ± 1.4 μΜ, V max = 0.65 ± 0.02 μmol mg protein(-1) h(-1)). Enhanced AR27 decolorization was observed with the increase of cell concentrations ranging from 7.5 to 45 mgL(-1). AR27 decolorization by G. metallireducens was retarded by the presence of goethite, which competed electrons with AR27 and was reduced to Fe(II). The addition of low concentrations of humic acid (1-100 mgL(-1)) or 2-hydroxy-1,4-naphthoquinone (0.5-50 μM) could improve the decolorization performance of G. metallireducens. High-performance liquid chromatography analysis suggested reductive pathway to be responsible for decolorization. This was the first study on azo dye decolorization by Geobacter strain and might improve our understanding of natural attenuation and bioremediation of environments polluted by azo dyes.

  19. The lipids of Pneumocystis carinii.

    PubMed

    Kaneshiro, E S

    1998-01-01

    Information about a number of Pneumocystis carinii lipids obtained by the analyses of organisms isolated and purified from infected lungs of corticosteroid-immunosuppressed rats has been reported in recent years. Of the common opportunistic protists associated with AIDS (Cryptosporidium, Toxoplasma, and the microsporidia), more is currently known about the lipids of P. carinii than the others. Lipids that are synthesized by the organism but not by humans are attractive targets for drug development. Thus, the elucidation of delta 7C-24-alykylated sterol and cis-9,10-epoxystearic acid biosyntheses in P. carinii is currently being examined in detail, since these have been identified as P. carinii-specific lipids. The development of low-toxicity drugs that prevent sterol C-24 alkylation and the specific inhibition of the lipoxygenase that forms cis-9,10-epoxystearic acid might prove fruitful. Although humans can synthesize coenzyme Q10, the anti-P. carinii activity and low toxicity of ubiquinone analogs such as atovaquone suggest that the electron transport chain in the pathogen may differ importantly from that in the host. Although resistance to atovaquone has been observed, development of other naphthoquinone drugs would provide a broader armamentarium of drugs to treat patients with P. carinii pneumonia. Studies of bronchoalveolar lavage fluid and of infected lungs have demonstrated that the infection causes a number of chemical abnormalities. Bronchoalveolar lavage fluid obtained after the removal of lung cellular material and the organisms has been shown to contain larger amounts of surfactant proteins and smaller amounts of phospholipids than do comparable samples from P. carinii-free lungs. Increased phospholipase activity, inhibition of surfactant secretion by type II cells, and uptake and catabolism of lipids by the pathogen may explain this phenomenon related to P. carinii pneumonia. Although not yet thoroughly examined, initial studies on the uptake and

  20. Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol

    SciTech Connect

    Maeda, Masayo; Murakami, Manabu; Takegami, Tsutomu; Ota, Takahide

    2008-06-01

    Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent.

  1. Functional anatomy of scent glands in Paranemastoma quadripunctatum (Opiliones, Dyspnoi, Nemastomatidae).

    PubMed

    Schaider, Miriam; Komposch, Christian; Stabentheiner, Edith; Raspotnig, Günther

    2011-10-01

    The morphological organization and functional anatomy of prosomal defensive (scent) glands in Paranemastoma quadripunctatum, a representative of the dyspnoid harvestmen, was investigated by means of histological semithin sections, software-based 3D-reconstruction and scanning electron microscopy. Scent glands comprise large, hollow sacs on either side of the prosoma, each of these opening to the outside via one orifice (ozopore) immediately above coxa I. In contrast to the situation known from laniatorean, cyphophthalmid and some eupnoid Opiliones, ozopores are not exposed but hidden in a depression (atrium), formed by a dorsal integumental fold of the carapace and the dorsal parts of coxae I. Glandular sacs are connected to ozopores via a short duct which is equipped with a specific closing mechanism in its distal part: A layer of modified epidermal cells forms a kind of pad-like tissue, surrounding the duct like a valve. Several muscles attached to the anterior parts of the glandular reservoir and to the epithelial pad may be associated with ozopore-opening. The actual mechanism of secretion discharge seems to be highly unusual and may be hypothesized on the basis of corroborating data from behavioral observations, scent gland anatomy and secretion chemistry as follows: Enteric fluid is considered to be directed towards the ozopores via cuticular grooves in the surface of the coxapophyses of legs I. Then, the fluid is sucked into the anterior part of the scent gland reservoirs by the action of dorsal dilator muscles that widen the reservoir and produce a short-term negative pressure. After dilution/solution of the naphthoquinone-rich scent gland contents, a secretion-loaded fluid is thought to be discharged with the help of transversal compressor muscles. This is the first detailed study on the functional anatomy of scent glands and the mechanisms of secretion discharge in the Dyspnoi. PMID:21618269

  2. Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health.

    PubMed

    Shearer, M J; Bach, A; Kohlmeier, M

    1996-04-01

    Vitamin K occurs in nature as a series of compounds with a common 2-methyl- 1,4 naphthoquinone nucleus and differing isoprenoid side chains at the 3 position. They comprise a single major plant form, phylloquinone with a phytyl side chain and a family of bacterially synthesized menaquinones (MKs) with multiprenyl side chains. The major dietary source to humans is phylloquinone for which the chief food contributors are green, leafy vegetables followed by certain vegetable oils (soybean, rapeseed and olive oils). Recent analyses by high pressure liquid chromatography are now providing a wide-ranging database of phylloquinone in foods. Menaquinones are found in moderate concentrations in only a few foods such as cheeses (MK-8 and MK-9). A wider spectrum of MKs is synthesized by the gut microflora, and their intestinal absorption probably accounts for most of the hepatic stores, particularly those with very long side chains (MKs-10--13) synthesized by members of the genus Bacteroides. The site of absorption of floral MKs is not known, but reasonable concentrations are found in the terminal ileum where bile salt-mediated absorption is possible. Both phylloquinone and menaquinones are bioactive in hepatic gamma-carboxylation but long-chain MKs are less well absorbed. Liver stores of vitamin K are relatively small and predominantly MKs-7--13. The hepatic reserves of phylloquinone (approximately 10% of the total) are labile and turn over at a faster rate than menaquinones. Trabecular and cortical bone appear to contain substantial concentrations of both phylloquinone and menaquinones. A majority (approximately 60-70%) of the daily dietary intake of phylloquinone is lost to the body by excretion, which emphasizes the need for a continuous dietary supply to maintain tissue reserves.

  3. Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice.

    PubMed

    Carratt, S A; Morin, D; Buckpitt, A R; Edwards, P C; Van Winkle, L S

    2016-03-30

    Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. 1,2-Dihydro-1,2-dihydroxynaphthalene (NA-dihydrodiol) is a major metabolite of NA generated by microsomal epoxide hydrolase (mEH). To investigate the role of the NA-dihydrodiol and subsequent metabolites (i.e. 1,2-naphthoquinone) in cytotoxicity, we exposed both male and female wild type (WT) and mEH null mice (KO) to NA by inhalation (5, 10, 20 ppm for 4h). NA-dihydrodiol was ablated in the KO mice. High-resolution histopathology was used to study site-specific cytotoxicity, and formation of naphthalene metabolites was measured by HPLC in microdissected airways. Swollen and vacuolated airway epithelial cells were observed in the intra- and extrapulmonary airways of all mice at and below the current OSHA standard (10 ppm). Female mice may be more susceptible to this acute cytotoxicity. In the extrapulmonary airways, WT mice were more susceptible to damage than KO mice, indicating that the metabolites associated with mEH-mediated metabolism could be partially responsible for cytotoxicity at this site. The level of cytotoxicity in the mEH KO mice at all airway levels suggests that non-mEH metabolites are contributing to NA cellular damage in the lung. Our results indicate that the apparent contribution of mEH-dependent metabolites to toxicity differs by location in the lung. These studies suggest that metabolites generated through the mEH pathway may be of minor importance in distal airway toxicity and subsequent carcinogenesis from NA exposure.

  4. Toxicological effects of polycyclic aromatic hydrocarbons and their derivatives on respiratory cells

    NASA Astrophysics Data System (ADS)

    Koike, Eiko; Yanagisawa, Rie; Takano, Hirohisa

    2014-11-01

    Polycyclic aromatic hydrocarbons (PAHs) are found in ambient aerosols and particulate matter. Experimental studies have shown that PAHs and related chemicals can induce toxicological effects. The present study aimed to investigate the effects of PAHs and their derivatives on the respiratory and immune systems and the underlying mechanisms. The human bronchial epithelial cell line BEAS-2B was exposed to PAHs and their derivatives, and the cytotoxicity and proinflammatory protein expression were then investigated. A cytotoxic effect was observed in BEAS-2B exposed to PAH derivatives such as naphthoquinone (NQ), phenanthrenequinone (PQ), 1-nitropyrene (1-NP), and 1-aminopyrene (1-AP). In addition, 1,2-NQ and 9,10-PQ showed more effective cytotoxicity than 1,4-NQ and 1,4-PQ, respectively. Pyrene showed a weak cytotoxic effect. On the other hand, naphthalene and phenanthrene showed no significant effects. Pyrene, 1-NP, and 1-AP also increased intercellular adhesion molecule-1 expression and interleukin-6 production in BEAS-2B. The increase was partly suppressed by protein kinase inhibitors such as the epidermal growth factor receptor-selective tyrosine kinase inhibitor and nuclear receptor antagonists such as the thyroid hormone receptor antagonist. The present study suggests that the toxicological effects of chemicals may be related to the different activities resulting from their structures, such as numbers of benzene rings and functional groups. Furthermore, the chemical-induced increase in proinflammatory protein expression in bronchial epithelial cells was possibly a result of the activation of protein kinase pathways and nuclear receptors. The increase may partly contribute to the adverse health effects of atmospheric PAHs.

  5. Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species

    PubMed Central

    San Martin Galindo, Paola; Taguchi, Takaaki; Manner, Suvi; Vuorela, Pia M.; Ichinose, Koji; Metsä-Ketelä, Mikko

    2015-01-01

    Streptomyces bacteria are renowned for their ability to produce bioactive secondary metabolites. Recently, synthetic biology has enabled the production of intermediates and shunt products, which may have altered biological activities compared to the end products of the pathways. Here, we have evaluated the potential of recently isolated alnumycins and other closely related pyranonaphthoquinone (PNQ) polyketides against Staphylococcus aureus biofilms. The antimicrobial potency of the compounds against planktonic cells and biofilms was determined by redox dye-based viability staining, and the antibiofilm efficacy of the compounds was confirmed by viable counting. A novel antistaphylococcal polyketide, alnumycin D, was identified. Unexpectedly, the C-ribosylated pathway shunt product alnumycin D was more active against planktonic and biofilm cells than the pathway end product alnumycin A, where a ribose unit has been converted into a dioxane moiety. The evaluation of the antibiofilm potential of other alnumycins revealed that the presence of the ribose moiety in pyranose form is essential for high activity against preformed biofilms. Furthermore, the antibiofilm potential of other closely related PNQ polyketides was examined. Based on their previously reported activity against planktonic S. aureus cells, granaticin B, kalafungin, and medermycin were also selected for testing, and among them, granaticin B was found to be the most potent against preformed biofilms. The most active antibiofilm PNQs, alnumycin D and granaticin B, share several structural features that may be important for their antibiofilm activity. They are uncharged, glycosylated, and also contain a similar oxygenation pattern of the lateral naphthoquinone ring. These findings highlight the potential of antibiotic biosynthetic pathways as a source of effective antibiofilm compounds. PMID:26195520

  6. Cooperation of NAD(P)H:quinone oxidoreductase 1 and UDP-glucuronosyltransferases reduces menadione cytotoxicity in HEK293 cells.

    PubMed

    Nishiyama, Takahito; Izawa, Tadashi; Usami, Mami; Ohnuma, Tomokazu; Ogura, Kenichiro; Hiratsuka, Akira

    2010-04-01

    Previous studies have shown that NAD(P)H:quinone oxidoreductase 1 (NQO1) plays an important role in the detoxification of menadione (2-methyl-1,4-naphthoquinone, also known as vitamin K3). However, menadiol (2-methyl-1,4-naphthalenediol) formed from menadione by NQO1-mediated reduction continues to be an unstable substance, which undergoes the reformation of menadione with concomitant formation of reactive oxygen species (ROS). Hence, we focused on the roles of phase II enzymes, with particular attention to UDP-glucuronosyltransferases (UGTs), in the detoxification process of menadione. In this study, we established an HEK293 cell line stably expressing NQO1 (HEK293/NQO1) and HEK293/NQO1 cell lines with doxycycline (DOX)-regulated expression of UGT1A6 (HEK293/NQO1/UGT1A6) and UGT1A10 (HEK293/NQO1/UGT1A10), and evaluated the role of NQO1 and UGTs against menadione-induced cytotoxicity. Our results differed from those of previous studies. HEK293/NQO1 was the most sensitive cell line to menadione cytotoxicity among cell lines established in this study. These phenomena were also observed in HEK293/NQO1/UGT1A6 and HEK293/NQO1/UGT1A10 cells in which the expression of UGT was suppressed by DOX treatment. On the contrary, HEK293/NQO1/UGT1A6 and HEK293/NQO1/UGT1A10 cells without DOX treatment were resistant to menadione-induced cytotoxicity. These results demonstrated that NQO1 is not a detoxification enzyme for menadione and that UGT-mediated glucuronidation of menadiol is the most important detoxification process.

  7. Improved resolution of thick film resist: effect of development technique

    NASA Astrophysics Data System (ADS)

    Sensu, Yoshihisa; Sekiguchi, Atsushi; Miyake, Yasuhiro

    2002-07-01

    In view of the fact that little analysis of the mechanism for the achievement of high resolution or a high aspect ratio in the thick-film resist process has been performed, we study development properties with respect to differences between the development methods employed for pattern formation using thick-film resist. This study identifies the most effective development method for thick-film resist and reports the mechanism of development. For this investigation, we use a development rate measurement system, a mask aligner, and lithography simulator to examine the dipping development method, the step puddle development method, the vibration development method, and the reverse development method. We employ a thick-film positive resist composed of diazo-naphthoquinone (DNQ) and Novolak resin, which is coated on a silicon substrate to a thickness of 24 micrometers . After pre-baking, the coated substrate is placed in a vacuum dessicator to remove water, followed by immersion in deionized water for a fixed period. A mask pattern is transferred to the resist coated substrate with a Mask Aligner Q4000 made by Quintel Corporation, and then the rate of development is measured. A laser microscope analysis of the result indicates that the step puddle development method gives the highest pattern resolution and sharpness, followed by the vibration development method, the dipping development method, and lastly the reverse development method. The mechanisms of the development are studied by comparing the development contrast and the energy of activation involved in each development method, and by conducting resist pattern simulations. The results indicate that the factors responsible for retarding the progression of the development process and causing a degradation of pattern profile and resolution are development inhibition due to N2 released from inside the resist during the development process, and due to products that are dissolved in the development solution.

  8. Molecular structures and biological evaluation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone derivatives as potent antifungal agents

    NASA Astrophysics Data System (ADS)

    Pawar, Omkar; Patekar, Ashwini; Khan, Ayesha; Kathawate, Laxmi; Haram, Santosh; Markad, Ganesh; Puranik, Vedavati; Salunke-Gawali, Sunita

    2014-02-01

    Derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} have been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-visible spectroscopy, LC-MS and single crystal X-ray diffraction studies. Antifungal activity of L-1 to L-4 has been evaluated against Candida tropicalis, Candida albicans and Cladosporium herbarum. The intramolecular hydrogen bonding affects the N-H vibrational frequency in L-2 (3273 cm-1). The single crystal X-ray structure reveal that L-1 and L-3 crystallizes in triclinic P-1, whereas L-2 crystallizes in orthorhombic Pca21 space group. An extensive intra and intermolecular hydrogen bonding interactions were observed in L-1 to L-3 which leads to molecular association. Intramolecular N-H⋯O hydrogen bonding were observed in L-1 to L-3. Moreover π-π stacking interactions were observed between the quinonoid rings of L-1 and L-3, however no such interactions were observed in L-2. An electrochemical study showed molecular association of L-1 to L-4 in DMSO solution. Compounds L-1 to L-4 were found to be potent antifungal agents against all the three strains, especially against C. tropicalis. Amongst these promising antifungal candidates, L-1 showed better activity compared to the clinically administered antifungal drug Amphotericin B and Nitrofurantoin with MIC = 1.25 μg ml-1 and MIC = 0.025 μg ml-1 respectively against C. albicans. Structure and activity relationship (SAR) study suggest a Log P value of ˜2.0 and the cyclic voltammetry studies reveals additional chemical processes for L-1, which exhibits maximum activity against all fungal strains.

  9. Ultrasonic nebulization extraction/low pressure photoionization mass spectrometry for direct analysis of chemicals in matrices.

    PubMed

    Liu, Chengyuan; Zhu, Yanan; Zhou, Zhongyue; Yang, Jiuzhong; Qi, Fei; Pan, Yang

    2015-09-01

    A novel ultrasonic nebulization extraction/low-pressure photoionization (UNE-LPPI) system has been designed and employed for the rapid mass spectrometric analysis of chemicals in matrices. An ultrasonic nebulizer was used to extract the chemicals in solid sample and nebulize the solvent in the nebulization cell. Aerosols formed by ultrasonic were evaporated by passing through a transferring tube, and desolvated chemicals were ionized by the emitted light (10.6 eV) from a Krypton discharge lamp at low pressure (∼68 Pa). First, a series of semi/non-volatile compounds with different polarities, such as polycyclic aromatic hydrocarbons (PAHs), amino acids, dipeptides, drugs, nucleic acids, alkaloids, and steroids were used to test the system. Then, the quantification capability of UNE-LPPI was checked with: 1) pure chemicals, such as 9,10-phenanthrenequinone and 1,4-naphthoquinone dissolved in solvent; 2) soil powder spiked with different amounts of phenanthrene and pyrene. For pure chemicals, the correlation coefficient (R(2)) for the standard curve of 9,10-phenanthrenequinone in the range of 3 ng-20 μg mL(-1) was 0.9922, and the measured limits of detection (LOD) was 1 ng ml(-1). In the case of soil powder, linear relationships for phenanthrene and pyrene from 10 to 400 ng mg(-1) were obtained with correlation coefficients of 0.9889 and 0.9893, respectively. At last, the feasibility of UNE-LPPI for the detection of chemicals in real matrices such as tablets and biological tissues (tea, Citrus aurantium peel and sage (Salvia officinalis) leaf) were successfully demonstrated. PMID:26388379

  10. Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells

    PubMed Central

    Fiorillo, Marco; Lamb, Rebecca; Tanowitz, Herbert B.; Mutti, Luciano; Krstic-Demonacos, Marija; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.

    2016-01-01

    Atovaquone is an FDA-approved anti-malarial drug, which first became clinically available in the year 2000. Currently, its main usage is for the treatment of pneumocystis pneumonia (PCP) and/or toxoplasmosis in immune-compromised patients. Atovaquone is a hydroxy-1,4-naphthoquinone analogue of ubiquinone, also known as Co-enzyme Q10 (CoQ10). It is a well-tolerated drug that does not cause myelo-suppression. Mechanistically, it is thought to act as a potent and selective OXPHOS inhibitor, by targeting the CoQ10-dependence of mitochondrial complex III. Here, we show for the first time that atovaquone also has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that atovaquone treatment of MCF7 breast cancer cells inhibits oxygen-consumption and metabolically induces aerobic glycolysis (the Warburg effect), as well as oxidative stress. Remarkably, atovaquone potently inhibits the propagation of MCF7-derived CSCs, with an IC-50 of 1 μM, as measured using the mammosphere assay. Atovaquone also maintains this selectivity and potency in mixed populations of CSCs and non-CSCs. Importantly, these results indicate that glycolysis itself is not sufficient to maintain the proliferation of CSCs, which is instead strictly dependent on mitochondrial function. In addition to targeting the proliferation of CSCs, atovaquone also induces apoptosis in both CD44+/CD24low/− CSC and ALDH+ CSC populations, during exposure to anchorage-independent conditions for 12 hours. However, it has no effect on oxygen consumption in normal human fibroblasts and, in this cellular context, behaves as an anti-inflammatory, consistent with the fact that it is well-tolerated in patients treated for infections. Future studies in xenograft models and human clinical trials may be warranted, as the IC-50 of atovaquone's action on CSCs (1 μM) is >50 times less than its average serum concentration in humans. PMID:27136895

  11. Dissimilar effects of β-lapachone- and hydroxyurea-induced DNA replication stress in root meristem cells of Allium cepa.

    PubMed

    Zabka, Aneta; Trzaskoma, Paweł; Maszewski, Janusz

    2013-12-01

    Two anticancer drugs, β-lapachone (β-lap, a naphthoquinone) and hydroxyurea (HU, an inhibitor of ribonucleotide reductase), differently affect nuclear morphology and cell cycle control mechanisms in root meristem cells of Allium cepa. The 18 h treatment with 100 μM β-lap results in a lowered number of M-phase cells, increased occurrence of mitotic abnormalities, including over-condensation of chromosomes, their enhanced stickiness, formation of anaphase bridges, micronucleation and reduced mitotic spindles. Following prolonged incubations using high doses of β-lap, cell nuclei reveal dark-red fluorescence evenly distributed in chromatin surrounding the unstained regions of nucleoli. Both drugs generate H2O2 and induce DNA double strand breaks, which is correlated with γ-phoshorylation of H2AX histones. However, the extent of H2AX phosphorylation (including the frequency of γ-H2AX foci and the relative number cells creating phospho-H2AX domains) is considerably reduced in root meristem cells treated jointly with the β-lap/HU mixture. Furthermore, various effects of caffeine (an inhibitor of ATM/ATR cell cycle checkpoint kinases) on β-lap- and HU-induced γ-phoshorylation of H2AX histones and the protective activity of HU against β-lap suggest that their genotoxic activities are largely dissimilar. β-Lap treatment results in the induction of apoptosis-like programmed cell death, while HU treatment leads to cell adaptation to replication stress and promotion of abnormal nuclear divisions with biphasic interphase/mitotic states of chromatin condensation.

  12. Electrodegradation of the Acid Green 28 dye using Ti/β-PbO2 and Ti-Pt/β-PbO2 anodes.

    PubMed

    Irikura, Kallyni; Bocchi, Nerilso; Rocha-Filho, Romeu C; Biaggio, Sonia R; Iniesta, Jesús; Montiel, Vicente

    2016-12-01

    The statistical Response Surface Methodology (RSM) is applied to investigate the effect of different parameters (current density, j, NaCl concentration, [NaCl], pH, and temperature, θ) and their interactions on the electrochemical degradation of the Acid Green (AG) 28 dye using a Ti/β-PbO2 or Ti-Pt/β-PbO2 anode in a filter-press reactor. LC/MS is employed to identify intermediate compounds. For both anodes, the best experimental conditions are j = 50 mA cm(-2), [NaCl] = 1.5 g L(-1), pH = 5, and θ = 25 °C. After 3 h of electrolysis, a dye solution treated under these conditions presents the following parameters: electric charge per unit volume of the electrolyzed solution required for 90% decolorization (Q(90)) of 0.34-0.37 A h L(-1), %COD removal of ∼100%, specific energy consumption of 18-20 kW h m(-3), and %TOC removal of 32-33%. No loss of the β-PbO2 film is observed during all the experiments. The β-PbO2 films present excellent stability for solutions with pH ≥ 5 ([Pb(2+)] < 0.5 mg L(-1)). Chloroform is the only volatile organic halo compound present in the treated solution under those optimized conditions. Hydroxylated anthraquinone derivatives, aromatic chloramines, and naphthoquinones are formed during the electrolyses. The Ti/β-PbO2 and Ti-Pt/β-PbO2 anodes show significantly better performance than a commercial DSA anode for the electrochemical degradation of the AG 28 dye. The Ti/β-PbO2 anode, prepared as described in this work, is an excellent option for the treatment of textile effluents because of its low cost of fabrication and good performance. PMID:27604754

  13. Antibacterial activities and structure-activity relationships of a panel of 48 compounds from Kenyan plants against multidrug resistant phenotypes.

    PubMed

    Omosa, Leonidah K; Midiwo, Jacob O; Mbaveng, Armelle T; Tankeo, Simplice B; Seukep, Jackson A; Voukeng, Igor K; Dzotam, Joachim K; Isemeki, John; Derese, Solomon; Omolle, Ruth A; Efferth, Thomas; Kuete, Victor

    2016-01-01

    In the current study forty eight compounds belonging to anthraquinones, naphthoquinones, benzoquinones, flavonoids (chalcones and polymethoxylated flavones) and diterpenoids (clerodanes and kauranes) were explored for their antimicrobial potential against a panel of sensitive and multi-drug resistant Gram-negative and Gram-positive bacteria. The minimal inhibitory concentration (MIC) determinations on the tested bacteria were conducted using modified rapid INT colorimetric assay. To evaluate the role of efflux pumps in the susceptibility of Gram-negative bacteria to the most active compounds, they were tested in the presence of phenylalanine arginine β-naphthylamide (PAβN) (at 30 µg/mL) against selected multidrug resistance (MDR) bacteria. The anthraquinone, emodin, naphthaquinone, plumbagin and the benzoquinone, rapanone were active against methicillin resistant Staphylococcus aureus (MRSA) strains of bacteria with MIC values ranging from 2 to 128 μg/mL. The structure activity relationships of benzoquinones against the MDR Gram-negative phenotype showed antibacterial activities increasing with increase in side chain length. In the chalcone series the presence of a hydroxyl group at C3' together with a methoxy group and a second hydroxyl group in meta orientation in ring B of the chalcone skeleton appeared to be necessary for minimal activities against MRSA. In most cases, the optimal potential of the active compounds were not attained as they were extruded by bacterial efflux pumps. However, the presence of the PAβN significantly increased the antibacterial activities of emodin against Gram-negative MDR E. coli AG102, 100ATet; K. pneumoniae KP55 and KP63 by >4-64 g/mL. The antibacterial activities were substantially enhanced and were higher than those of the standard drug, chloramphenicol. These data clearly demonstrate that the active compounds, having the necessary pharmacophores for antibacterial activities, including some quinones and chalcones are

  14. Understanding amyloid fibril nucleation and aβ oligomer/drug interactions from computer simulations.

    PubMed

    Nguyen, Phuong; Derreumaux, Philippe

    2014-02-18

    the critical nucleus size might be on the order of 20 chains under physiological conditions. The transition state might be characterized by a simultaneous change from mixed antiparallel/parallel β-strands with random side-chain packing to the final antiparallel or parallel states with the steric zipper packing of the side chains. Second, we review our current computer-based knowledge of the 3D structures of inhibitors with Aβ42 monomer and oligomers, a prerequisite for developing new drugs against AD. Recent extensive all-atom simulations of Aβ42 dimers with known inhibitors such as the green tea compound epigallocatechin-3-gallate and 1,4-naphthoquinon-2-yl-l-tryptophan provide a spectrum of initial Aβ42/inhibitor structures useful for screening and drug design. We conclude by discussing future directions that may offer opportunities to fully understand nucleation and further AD drug development.

  15. YY1 positively regulates human UBIAD1 expression

    SciTech Connect

    Funahashi, Nobuaki; Hirota, Yoshihisa; Nakagawa, Kimie; Sawada, Natumi; Watanabe, Masato; Suhara, Yoshitomo; Okano, Toshio

    2015-05-01

    Vitamin K is involved in bone formation and blood coagulation. Natural vitamin K compounds are composed of the plant form phylloquinone (vitamin K{sub 1}) and a series of bacterial menaquionones (MK-n; vitamin K{sub 2}). Menadione (vitamin K{sub 3}) is an artificial vitamin K compound. MK-4 contains 4-isoprenyl as a side group in the 2-methyl-1,4-naphthoquinone common structure and has various bioactivities. UbiA prenyltransferase domain containing 1 (UBIAD1 or TERE1) is the menaquinone-4 biosynthetic enzyme. UBIAD1 transcript expression significantly decreases in patients with prostate carcinoma and overexpressing UBIAD1 inhibits proliferation of a tumour cell line. UBIAD1 mRNA expression is ubiquitous in mouse tissues, and higher UBIAD1 mRNA expression levels are detected in the brain, heart, kidneys and pancreas. Several functions of UBIAD1 have been reported; however, regulation of the human UBIAD1 gene has not been elucidated. Here we report cloning and characterisation of the human UBIAD1 promoter. A 5′ rapid amplification of cDNA ends analysis revealed that the main transcriptional start site was 306 nucleotides upstream of the translation initiation codon. Deletion and mutation analyses revealed the functional importance of the YY1 consensus motif. Electrophoretic gel mobility shift and chromatin immunoprecipitation assays demonstrated that YY1 binds the UBIAD1 promoter in vitro and in vivo. In addition, YY1 small interfering RNA decreased endogenous UBIAD1 mRNA expression and UBIAD1 conversion activity. These results suggest that YY1 up-regulates UBIAD1 expression and UBIAD1 conversion activity through the UBIAD1 promoter. - Highlights: • We cloned the human UBIAD1 promoter. • The functional importance of the YY1 motif was identified in the UBIAD1 promoter. • YY1 binds the UBIAD1 promoter in vitro and in vivo. • Knockdown of YY1 significantly decreased UBIAD1 expression. • YY1 up-regulates UBIAD1 conversion activity through the UBIAD1

  16. Menadione cytotoxicity to Hep G2 cells and protection by activation of nuclear factor-kappaB.

    PubMed

    Chen, Q; Cederbaum, A I

    1997-10-01

    Menadione (vitamin K-3,2-methyl-1,4-naphthoquinone), a redox cycling reagent, generates reactive oxygen intermediates and causes oxidative injury. The addition of menadione to Hep G2 cells produced a time- and concentration-dependent loss of cell viability. Preincubation of Hep G2 cells with low, nontoxic concentrations of menadione increased the viability of the cells against toxic doses of menadione or H2O2. Maximum protection was found with menadione concentrations of approximately 3 microM and preincubation times of approximately 45 min. This protective effect could be blocked by the protein synthesis inhibitor cycloheximide and by a variety of antioxidants. The transcription factor nuclear factor-kappaF (NF-kappaB) is known to be activated by many compounds, including reactive oxygen intermediates. Menadione activated NF-kappaB as determined by electrophoretic mobility shift assays. This activation was prevented by the same antioxidants that blocked protection against cytotoxicity produced by preincubation with menadione. Anti-p50 IgG prevented the menadione-stimulated binding of NF-kappaB to the oligonucleotide probe, whereas anti-p65 IgG produced a supershift of the NF-kappaB/oligonucleotide complex. Salicylate prevented the activation of NF-kappaB by menadione, and under these conditions, salicylate potentiated the cytotoxicity of menadione or H2O2. Transfection with a plasmid containing cDNA encoding mouse IkappaBbeta, an inhibitor of NF-kappaB, resulted in increased toxicity by menadione. Furthermore, when protein kinase C was down-regulated by prolonged treatment with active phorbol ester (phorbol-12-myristate-13-acetate), the Hep G2 cells became more sensitive to menadione treatment. However, short term treatment with PMA, which activated NF-kappaB, resulted in protection against menadione cytotoxicity. Menadione cytotoxicity was enhanced when the Hep G2 cells were depleted of GSH. An increased level of GSH was observed after menadione pretreatment

  17. High glucose-induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects.

    PubMed

    Yu, Jingwen; Wu, Yanqing; Yang, Peixin

    2016-05-01

    Aberrant epigenetic modifications are implicated in maternal diabetes-induced neural tube defects (NTDs). Because cellular stress plays a causal role in diabetic embryopathy, we investigated the possible role of the stress-resistant sirtuin (SIRT) family histone deacetylases. Among the seven sirtuins (SIRT1-7), pre-gestational maternal diabetes in vivo or high glucose in vitro significantly reduced the expression of SIRT 2 and SIRT6 in the embryo or neural stem cells, respectively. The down-regulation of SIRT2 and SIRT6 was reversed by superoxide dismutase 1 (SOD1) over-expression in the in vivo mouse model of diabetic embryopathy and the SOD mimetic, tempol and cell permeable SOD, PEGSOD in neural stem cell cultures. 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), a superoxide generating agent, mimicked high glucose-suppressed SIRT2 and SIRT6 expression. The acetylation of histone 3 at lysine residues 56 (H3K56), H3K14, H3K9, and H3K27, putative substrates of SIRT2 and SIRT6, was increased by maternal diabetes in vivo or high glucose in vitro, and these increases were blocked by SOD1 over-expression or tempol treatment. SIRT2 or SIRT6 over-expression abrogated high glucose-suppressed SIRT2 or SIRT6 expression, and prevented the increase in acetylation of their histone substrates. The potent sirtuin activator (SRT1720) blocked high glucose-increased histone acetylation and NTD formation, whereas the combination of a pharmacological SIRT2 inhibitor and a pan SIRT inhibitor mimicked the effect of high glucose on increased histone acetylation and NTD induction. Thus, diabetes in vivo or high glucose in vitro suppresses SIRT2 and SIRT6 expression through oxidative stress, and sirtuin down-regulation-induced histone acetylation may be involved in diabetes-induced NTDs. The mechanism underlying pre-gestational diabetes-induced neural tube defects (NTDs) is still elusive. Our study unravels a new epigenetic mechanism in which maternal diabetes-induced oxidative stress represses

  18. Details in the catalytic mechanism of mammalian thioredoxin reductase 1 revealed using point mutations and juglone-coupled enzyme activities.

    PubMed

    Xu, Jianqiang; Cheng, Qing; Arnér, Elias S J

    2016-05-01

    The mammalian selenoprotein thioredoxin reductase 1 (TrxR1) is a key enzyme in redox regulation, antioxidant defense, and cellular growth. TrxR1 can catalyze efficient reduction of juglone (5-hydroxy-1,4-naphthoquinone; walnut toxin) in a reaction which, in contrast to reduction of most other substrates of TrxR1, is not dependent upon an intact selenocysteine (Sec, U) residue of the enzyme. Using a number of TrxR1 mutant variants, we here found that a sole Cys residue at the C-terminal tail of TrxR1 is required for high-efficiency juglone-coupled NADPH oxidase activity of Sec-deficient enzyme, occurring with mixed one- and two-electron reactions producing superoxide. The activity also utilizes the FAD and the N-terminal redox active disulfide/dithiol motif of TrxR1. If a sole Cys residue at the C-terminal tail of TrxR1, in the absence of Sec, was moved further towards the C-terminal end of the protein compared to its natural position at residue 497, juglone reduction was, surprisingly, further increased. Ala substitutions of Trp407, Asn418 and Asn419 in a previously described "guiding bar", thought to mediate interactions of the C-terminal tail of TrxR1 with the FAD/dithiol site at the N-terminal domain of the other subunit in the dimeric enzyme, lowered turnover with juglone about 4.5-fold. Four residues of Sec-deficient TrxR1 were found to be easily arylated by juglone, including the Cys residue at position 497. Based upon our observations we suggest a model for involvement of the juglone-arylated C-terminal motif of TrxR1 to explain its high activity with juglone. This study thus provides novel insights into the catalytic mechanisms of TrxR1. One-electron juglone reduction by TrxR1 producing superoxide should furthermore contribute to the well-known prooxidant cytotoxicity of juglone. PMID:26898501

  19. Synthesis, characterization, and photocatalytic activities of Cobalt(II)-Titanium dioxide nanorods, and electrophoretic deposition of Titanium dioxide nanoparticle/nanorod composite films for self-cleaning applications

    NASA Astrophysics Data System (ADS)

    Kang, Wonjun

    This dissertation consists of two projects. The first project is synthesis, characterization, and photocatalytic activities of Co(II)-TiO2 nanorods. We modified brookite TiO2 nanorods with cobalt(II) ions to design new photocatalysts with visible light absorption. X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS) data indicated that the local structure of Co(II)-TiO2 nanorods was shown as tetrahedral and octahedral Co(II) sites at TiO2 nanorod surface. Dimethylglyoxime (DMG) has been used to remove surface Co(II) from Co(II)-TiO2 nanorods to determine single-site Co(II) ions selectively attached to the TiO 2 nanorod surface. We proposed a mechanism that the Co-Co bond of the precursor Co2(CO)8 undergoes heterolysis followed by disproportionation of Co(I) to produce Co(II) and Co(0) precipitate. Finally, the Co(II)-TiO2 nanorods showed greater activity than TiO 2 nanorods in the degradation of 5,8-dihydroxy-1,4-naphthoquinone (DHNQ) dye under visible light irradiation. The second project is electrophoretic deposition (EPD) of TiO2 nanoparticle/nanorod composite films for self-cleaning applications. We developed novel electrolyte system for EPD of TiO2 nanoparticle/nanorod composites for self-cleaning coatings. A mixture of TiO2 powder and TiO2 nanorods was used as EPD suspension in a mixture of THF and acetone. TiO2 nanoparticle/nanorod composite films were fabricated on aluminium substrates via the EPD method, and were characterized by scanning electron microscope (SEM). SEM images showed that TiO2 nanoparticle/nanorod composite films had a uniform pore structure. The hydrophobic properties of surfaces in TiO2 nanoparticle/nanorod composite films were evaluated by water contact angle measurements. It was found that the surfaces of TiO2 nanoparticle/nanorod composite films were hydrophobic with contact angle of 103°. These hydrophobic surfaces are expected to have potential applications for self-cleaning.

  20. Investigations of solvent properties and solvent effects on chemical equilibria and reaction rates

    NASA Astrophysics Data System (ADS)

    Defeo, Laura Lynn Thomas

    Thermodynamic and structural properties computed via simulations of pure liquids and dilute solutions are routinely used as a metric of accuracy for condensed-phase force fields and in the development and testing of new methodology. Additionally, reliable modeling of solvent systems is critical to investigations of physical phenomena, such as the elucidation of solvent effects on chemical equilibria and reaction rates. This dissertation highlights a series of studies that span these topics. The Lennard-Jones 12-6 functional form, often invoked to model van der Waals interactions, has been argued to be too repulsive at short internuclear separations. Monte Carlo simulations of organic liquids at various temperatures and pressures show that this function, in conjunction with OPLS parameters, is capable of reproducing experimental densities. In order to address potential cumulative deviations of computed properties and conformational differences between the gas phase and pure liquids, Monte Carlo simulations have been carried out for the homologous n-alkane series C4H10-C12H26 using the OPLS-AA force field. Favorable structural motifs of longer alkanes were also investigated to study self solvation in the gas phase. Next, an overview of the computation of free energy changes in solution using perturbation theory, overlap sampling, and related approximate methods is presented. Results are provided for free energies of hydration of OPLS-AA substituted benzenes in TIP4P water. For comparable amounts of computer time, the double-wide and overlap sampling methods yield very similar results. QM/MM simulations of the Diels-Alder reactions of cyclopentadiene with 1,4-naphthoquinone, methyl vinyl ketone, and acrylonitrile have been carried out at the water-vacuum interface and in the gas phase. The relative free energies of activation and transition structure geometries at the interface were intermediate between those calculated in the gas phase and in bulk water, consistent

  1. Naphthalene distributions and human exposure in Southern California

    NASA Astrophysics Data System (ADS)

    Lu, Rong; Wu, Jun; Turco, Richard P.; Winer, Arthur M.; Atkinson, Roger; Arey, Janet; Paulson, Suzanne E.; Lurmann, Fred W.; Miguel, Antonio H.; Eiguren-Fernandez, Arantzazu

    may occur for individuals close to local sources, or in naphthalene "hotspots" revealed by simulations and observations. Such levels of naphthalene exposure may be used to gauge the potential health impacts of long-term naphthalene exposure. Results are also given for the distributions of 1,4-naphthoquinone, a naphthalene reaction product that may have significant health effects.

  2. Reactive Oxygen Species Production Mediated by Humic-like Substances in Atmospheric Aerosols: Enhancement Effects by Pyridine, Imidazole, and Their Derivatives.

    PubMed

    Dou, Jing; Lin, Peng; Kuang, Bin-Yu; Yu, Jian Zhen

    2015-06-01

    Ambient particulate matter (PM) can cause adverse health effects via their ability to produce reactive oxygen species (ROS). Humic-like substances (HULIS), a complex mixture of amphiphilic organic compounds, have been demonstrated to contain the majority of redox activity in the water-extractable organic fraction of PM. Reduced organic nitrogen compounds, such as alkaloids resulting from biomass burning emissions, are among HULIS constituents. In this study, we examined the redox activities of pyridine, imidazole and their alkyl derivatives using a cell-free dithiothreitol (DTT) assay under simulated physiological conditions (37 °C, pH = 7.40). These compounds were found to have little redox activity on their own as measured by the DTT assay, but they enhanced ROS generation catalyzed by 1,4-naphthoquinone (as a model quinone compound) and HULIS isolated from multiple aerosol samples. The enhancement effect by the individual nitrogen-containing bases was determined to be proportional to their amount in the assay solutions. It is postulated that the underlying mechanism involves the unprotonated N atom acting as a H-bonding acceptor to facilitate hydrogen-atom transfer in the ROS generation cycle. The enhancement capability was found to increase with their basicity (i.e., pKa of their conjugated acids, BH(+)), consistent with the proposed mechanism for enhancement. Among the imidazole homologues, a linear relationship was observed between the enhancement factors (in log scale) of the unprotonated form of the imidazole compounds (B) and the pKa of their conjugated acids (BH(+)). This relationship predicts that the range of alkylimidazole homologues (C6-C13) observed in atmospheric HULIS would be 1.5-4.4 times more effective than imidazole in facilitating HULIS-mediated ROS generation. Our work reveals that the ability of atmospheric PM organics to catalyze generation of ROS in cells could be affected by coexisting redox inactive organic constituents and suggests

  3. Shikonin suppresses ERK 1/2 phosphorylation during the early stages of adipocyte differentiation in 3T3-L1 cells

    PubMed Central

    2013-01-01

    Background The naphthoquinone pigment, shikonin, is a major component of Lithospermum erythrorhizon and has been shown to have various biological functions, including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we investigated the effect of shikonin on adipocyte differentiation and its mechanism of action in 3T3-L1 cells. Methods To investigate the effects of shikonin on adipocyte differentiation, 3T3-L1 cells were induced to differentiate using 3-isobutyl-1-methylzanthine, dexamethasone, and insulin (MDI) for 8 days in the presence of 0–2 μM shikonin. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the anti-adipogenic mechanism of shikonin, adipogenic transcription factors, the phosphorylation levels of ERK, and adipogenic gene expression were analyzed by Western blotting and quantitative real-time PCR. To further confirm that shikonin inhibits adipogenic differentiation through downregulation of ERK 1/2 activity, 3T3-L1 cells were treated with shikonin in the presence of FGF-2, an activator, or PD98059, an inhibitor, of the ERK1/2 signaling pathway. Results Shikonin effectively suppressed adipogenesis and downregulated the protein levels of 2 major transcription factors, PPARγ and C/EBPα, as well as the adipocyte specific gene aP2 in a dose-dependent manner. qRT-PCR analysis revealed that shikonin inhibited mRNA expression of adipogenesis-related genes, such as PPARγ, C/EBPα, and aP2. Adipocyte differentiation was mediated by ERK 1/2 phosphorylation, which was confirmed by pretreatment with PD98059 (an ERK 1/2 inhibitor) or FGF-2 (an ERK 1/2 activator). The phosphorylation of ERK1/2 during the early stages of adipogenesis in 3T3-L1 cells was inhibited by shikonin. We also confirmed that FGF-2-stimulated ERK 1/2 activity was attenuated by shikonin. Conclusions These results demonstrate that shikonin inhibits adipogenic differentiation via suppression of the ERK signaling pathway

  4. Structural-functional characterization and physiological significance of ferredoxin-NADP reductase from Xanthomonas axonopodis pv. citri.

    PubMed

    Tondo, María Laura; Musumeci, Matías A; Delprato, María Laura; Ceccarelli, Eduardo A; Orellano, Elena G

    2011-01-01

    Xanthomonas axonopodis pv. citri is a phytopathogen bacterium that causes severe citrus canker disease. Similar to other phytopathogens, after infection by this bacterium, plants trigger a defense mechanism that produces reactive oxygen species. Ferredoxin-NADP(+) reductases (FNRs) are redox flavoenzymes that participate in several metabolic functions, including the response to reactive oxygen species. Xanthomonas axonopodis pv. citri has a gene (fpr) that encodes for a FNR (Xac-FNR) that belongs to the subclass I bacterial FNRs. The aim of this work was to search for the physiological role of this enzyme and to characterize its structural and functional properties. The functionality of Xac-FNR was tested by cross-complementation of a FNR knockout Escherichia coli strain, which exhibit high susceptibility to agents that produce an abnormal accumulation of (•)O(2)(-). Xac-FNR was able to substitute for the FNR in E. coli in its antioxidant role. The expression of fpr in X. axonopodis pv. citri was assessed using semiquantitative RT-PCR and Western blot analysis. A 2.2-fold induction was observed in the presence of the superoxide-generating agents methyl viologen and 2,3-dimethoxy-1,4-naphthoquinone. Structural and functional studies showed that Xac-FNR displayed different functional features from other subclass I bacterial FNRs. Our analyses suggest that these differences may be due to the unusual carboxy-terminal region. We propose a further classification of subclass I bacterial FNRs, which is useful to determine the nature of their ferredoxin redox partners. Using sequence analysis, we identified a ferredoxin (XAC1762) as a potential substrate of Xac-FNR. The purified ferredoxin protein displayed the typical broad UV-visible spectrum of [4Fe-4S] clusters and was able to function as substrate of Xac-FNR in the cytochrome c reductase activity. Our results suggest that Xac-FNR is involved in the oxidative stress response of Xanthomonas axonopodis pv. citri and

  5. Taurine reduction in anaerobic respiration of Bilophila wadsworthia RZATAU.

    PubMed

    Laue, H; Denger, K; Cook, A M

    1997-05-01

    Organosulfonates are important natural and man-made compounds, but until recently (T. J. Lie, T. Pitta, E. R. Leadbetter, W. Godchaux III, and J. R. Leadbetter. Arch. Microbiol. 166:204-210, 1996), they were not believed to be dissimilated under anoxic conditions. We also chose to test whether alkane- and arenesulfonates could serve as electron sinks in respiratory metabolism. We generated 60 anoxic enrichment cultures in mineral salts medium which included several potential electron donors and a single organic sulfonate as an electron sink, and we used material from anaerobic digestors in communal sewage works as inocula. None of the four aromatic sulfonates, the three unsubstituted alkanesulfonates, or the N-sulfonate tested gave positive enrichment cultures requiring both the electron donor and electron sink for growth. Nine cultures utilizing the natural products taurine, cysteate, or isethionate were considered positive for growth, and all formed sulfide. Two clearly different pure cultures were examined. Putative Desulfovibrio sp. strain RZACYSA, with lactate as the electron donor, utilized sulfate, aminomethanesulfonate, taurine, isethionate, and cysteate, converting the latter to ammonia, acetate, and sulfide. Strain RZATAU was identified by 16S rDNA analysis as Bilophila wadsworthia. In the presence of, e.g., formate as the electron donor, it utilized, e.g., cysteate and isethionate and converted taurine quantitatively to cell material and products identified as ammonia, acetate, and sulfide. Sulfite and thiosulfate, but not sulfate, were utilized as electron sinks, as was nitrate, when lactate was provided as the electron donor and carbon source. A growth requirement for 1,4-naphthoquinone indicates a menaquinone electron carrier, and the presence of cytochrome c supports the presence of an electron transport chain. Pyruvate-dependent disappearance of taurine from cell extracts, as well as formation of alanine and release of ammonia and acetate, was

  6. Identification of natural inhibitors of Entamoeba histolytica cysteine synthase from microbial secondary metabolites

    PubMed Central

    Mori, Mihoko; Jeelani, Ghulam; Masuda, Yui; Sakai, Kazunari; Tsukui, Kumiko; Waluyo, Danang; Tarwadi; Watanabe, Yoshio; Nonaka, Kenichi; Matsumoto, Atsuko; Ōmura, Satoshi; Nozaki, Tomoyoshi; Shiomi, Kazuro

    2015-01-01

    Amebiasis is a common worldwide diarrheal disease, caused by the protozoan parasite, Entamoeba histolytica. Metronidazole has been a drug of choice against amebiasis for decades despite its known side effects and low efficacy against asymptomatic cyst carriers. E. histolytica is also capable of surviving sub-therapeutic levels of metronidazole in vitro. Novel drugs with different mode of action are therefore urgently needed. The sulfur assimilatory de novo L-cysteine biosynthetic pathway is essential for various cellular activities, including the proliferation and anti-oxidative defense of E. histolytica. Since the pathway, consisting of two reactions catalyzed by serine acetyltransferase (SAT) and cysteine synthase (CS, O-acetylserine sulfhydrylase), does not exist in humans, it is a rational drug target against amebiasis. To discover inhibitors against the CS of E. histolytica (EhCS), the compounds of Kitasato Natural Products Library were screened against two recombinant CS isozymes: EhCS1 and EhCS3. Nine compounds inhibited EhCS1 and EhCS3 with IC50 values of 0.31–490 μM. Of those, seven compounds share a naphthoquinone moiety, indicating the structural importance of the moiety for binding to the active site of EhCS1 and EhCS3. We further screened >9,000 microbial broths for CS inhibition and purified two compounds, xanthofulvin and exophillic acid from fungal broths. Xanthofulvin inhibited EhCS1 and EhCS3. Exophillic acid showed high selectivity against EhCS1, but exhibited no inhibition against EhCS3. In vitro anti-amebic activity of the 11 EhCS inhibitors was also examined. Deacetylkinamycin C and nanaomycin A showed more potent amebicidal activity with IC50 values of 18 and 0.8 μM, respectively, in the cysteine deprived conditions. The differential sensitivity of trophozoites against deacetylkinamycin C in the presence or absence of L-cysteine in the medium and the IC50 values against EhCS suggest the amebicidal effect of deacetylkinamycin C is due to

  7. Electrodegradation of the Acid Green 28 dye using Ti/β-PbO2 and Ti-Pt/β-PbO2 anodes.

    PubMed

    Irikura, Kallyni; Bocchi, Nerilso; Rocha-Filho, Romeu C; Biaggio, Sonia R; Iniesta, Jesús; Montiel, Vicente

    2016-12-01

    The statistical Response Surface Methodology (RSM) is applied to investigate the effect of different parameters (current density, j, NaCl concentration, [NaCl], pH, and temperature, θ) and their interactions on the electrochemical degradation of the Acid Green (AG) 28 dye using a Ti/β-PbO2 or Ti-Pt/β-PbO2 anode in a filter-press reactor. LC/MS is employed to identify intermediate compounds. For both anodes, the best experimental conditions are j = 50 mA cm(-2), [NaCl] = 1.5 g L(-1), pH = 5, and θ = 25 °C. After 3 h of electrolysis, a dye solution treated under these conditions presents the following parameters: electric charge per unit volume of the electrolyzed solution required for 90% decolorization (Q(90)) of 0.34-0.37 A h L(-1), %COD removal of ∼100%, specific energy consumption of 18-20 kW h m(-3), and %TOC removal of 32-33%. No loss of the β-PbO2 film is observed during all the experiments. The β-PbO2 films present excellent stability for solutions with pH ≥ 5 ([Pb(2+)] < 0.5 mg L(-1)). Chloroform is the only volatile organic halo compound present in the treated solution under those optimized conditions. Hydroxylated anthraquinone derivatives, aromatic chloramines, and naphthoquinones are formed during the electrolyses. The Ti/β-PbO2 and Ti-Pt/β-PbO2 anodes show significantly better performance than a commercial DSA anode for the electrochemical degradation of the AG 28 dye. The Ti/β-PbO2 anode, prepared as described in this work, is an excellent option for the treatment of textile effluents because of its low cost of fabrication and good performance.

  8. Seasonal nutrient dynamics in the Anacostia River (D.C., USA): geochemistry and hydrocarbon biomarkers

    NASA Astrophysics Data System (ADS)

    Sarraino, S.; Frantz, D. E.; Macavoy, S. E.

    2010-12-01

    The seasonal biogeochemistry of the urban Anacostia River (Washington D.C. USA) was investigated. Chemical parameters examined include: inorganics (Ca, Mg, Na, S, K, P, NO3, NH4, PO4, B, Ba, Ni, Co); fatty acids and other hydrocarbons; C, N and S stable isotopes; and other water chemistry indicators (hardness, salinity, alkalinity, soluble salts, SAR, TDS). Between April and July 2010, water and sediment were sampled from three tidal freshwater sites along the Anacostia River (UP, MID, and DWN). Two of the selected sites, UP and DWN, are located next to a combined sewage outflow. Water column nutrient analysis shows increasing availability of ammonium (NH4) and nitrate (NO3) at all sites between April and July. At MID, the site showing the highest rates of nutrient growth over the sampling period, NH4 concentrations increase from 0.13 to 1.49 µg/L and NO3 concentrations increase from 0.71 to 2.88 mg/L. A marked NO3 pulse is observed at the DWN site in early May; NO3 concentrations jump from 0.68 to 3.36 mg/L between April 5 and May 6, decreasing to 1.22 mg/L by May 20. Unlike UP and MID, which show NH4 and NO3 increasing concurrently, this NO3 pulse at DWN is accompanied with a decline in NH4 levels, suggestive of an allochthonous NO3 source. Forthcoming stable isotope data are expected to characterize the source of such nitrogen inputs, as well as organic material, throughout the year. Preliminary GC-MS analysis of isolated fatty acids does not explicitly suggest bacterial or higher plant dominance in the spring; however, some notable compounds were identified, such as the PAH fluoranthene, naphthoquinone, and testosterone, as well as a number of cholesterols and other steroids. Higher proportions of bacterial fatty acid biomarkers are expected during the summer. Principle Component Analysis (PCA) of the chemistry data suggests geochemical variables, rather than nutrients, are the driving forces of observed trends. PCA, along with fatty acid characterization and

  9. Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

    SciTech Connect

    Bogen, K T

    2007-01-30

    As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate ''linear'' (genotoxic) vs. ''nonlinear'' (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach--similar to that used in reference dose procedures for classic toxicity endpoints--can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a ''nonlinear'' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Resulting bounds each provided the basis for a corresponding

  10. Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

    SciTech Connect

    Bogen, K T

    2007-05-11

    stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat rat-tumor tumor-type specific DMOA DMOA-related uncertainty were obtained using a 2-stage model adapted to reflec reflect the empirical link between genotoxic and cytotoxic effects of t the most potent identified genotoxic naphthalene metabolites, 1,2 1,2- and 1,4 1,4-naphthoquinone. Bound Bound-specific 'adjustment' factors were then used to reduce naphthalene risk estimated by linear ex extrapolation (under the default genotoxic MOA assumption), to account for the DMOA trapolation exhibited by this compound.

  11. Plumbagin induces cell cycle arrest and autophagy and suppresses epithelial to mesenchymal transition involving PI3K/Akt/mTOR-mediated pathway in human pancreatic cancer cells

    PubMed Central

    Wang, Feng; Wang, Qi; Zhou, Zhi-Wei; Yu, Song-Ning; Pan, Shu-Ting; He, Zhi-Xu; Zhang, Xueji; Wang, Dong; Yang, Yin-Xue; Yang, Tianxing; Sun, Tao; Li, Min; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2015-01-01

    Plumbagin (PLB), an active naphthoquinone compound, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of PLB for the treatment of pancreatic cancer is unclear. This study aimed to examine the pancreatic cancer cell killing effect of PLB and investigate the underlying mechanism in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that PLB exhibited potent inducing effects on cell cycle arrest in PANC-1 and BxPC-3 cells via the modulation of cell cycle regulators including CDK1/CDC2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. PLB treatment concentration- and time-dependently increased the percentage of autophagic cells and significantly increased the expression level of phosphatase and tensin homolog, beclin 1, and the ratio of LC3-II over LC3-I in both PANC-1 and BxPC-3 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin and p38 mitogen-activated protein kinase (p38 MAPK) pathways and activation of 5′-AMP-dependent kinase as indicated by their altered phosphorylation, contributing to the proautophagic activities of PLB in both cell lines. Furthermore, SB202190, a selective inhibitor of p38 MAPK, and wortmannin, a potent, irreversible, and selective PI3K inhibitor, remarkably enhanced PLB-induced autophagy in PANC-1 and BxPC-3 cells, indicating the roles of PI3K and p38 MAPK mediated signaling pathways in PLB-induced autophagic cell death in both cell lines. In addition, PLB significantly inhibited epithelial to mesenchymal transition phenotype in both cell lines with an increase in the expression level of E-cadherin and a decrease in N-cadherin. Moreover, PLB treatment significantly suppressed the expression of Sirt1 in both cell lines. These findings show that PLB promotes cell cycle arrest and autophagy but inhibits epithelial to mesenchymal transition phenotype in pancreatic cancer cells with the involvement of