Growth inhibitory effects of 3′-nitro-3-phenylamino nor-beta-lapachone against HL-60: A redox-dependent mechanism

AbstractIn this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3′-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO2) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF4) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO2. QPhNO2 caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO2 treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry

NEOTROPICAL XENARTHRANS: a data set of occurrence of xenarthran species in the Neotropics

Xenarthrans – anteaters, sloths, and armadillos – have essential functions for ecosystem maintenance, such as insect control and nutrient cycling, playing key roles as ecosystem engineers. Because of habitat loss and fragmentation, hunting pressure, and conflicts with 24 domestic dogs, these species have been threatened locally, regionally, or even across their full distribution ranges. The Neotropics harbor 21 species of armadillos, ten anteaters, and six sloths. Our dataset includes the families Chlamyphoridae (13), Dasypodidae (7), Myrmecophagidae (3), Bradypodidae (4), and Megalonychidae (2). We have no occurrence data on Dasypus pilosus (Dasypodidae). Regarding Cyclopedidae, until recently, only one species was recognized, but new genetic studies have revealed that the group is represented by seven species. In this data-paper, we compiled a total of 42,528 records of 31 species, represented by occurrence and quantitative data, totaling 24,847 unique georeferenced records. The geographic range is from the south of the USA, Mexico, and Caribbean countries at the northern portion of the Neotropics, to its austral distribution in Argentina, Paraguay, Chile, and Uruguay. Regarding anteaters, Myrmecophaga tridactyla has the most records (n=5,941), and Cyclopes sp. has the fewest (n=240). The armadillo species with the most data is Dasypus novemcinctus (n=11,588), and the least recorded for Calyptophractus retusus (n=33). With regards to sloth species, Bradypus variegatus has the most records (n=962), and Bradypus pygmaeus has the fewest (n=12). Our main objective with Neotropical Xenarthrans is to make occurrence and quantitative data available to facilitate more ecological research, particularly if we integrate the xenarthran data with other datasets of Neotropical Series which will become available very soon (i.e. Neotropical Carnivores, Neotropical Invasive Mammals, and Neotropical Hunters and Dogs). Therefore, studies on trophic cascades, hunting pressure, habitat loss, fragmentation effects, species invasion, and climate change effects will be possible with the Neotropical Xenarthrans dataset

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

Growth Inhibitory Effects Of 3'-nitro-3-phenylamino Nor-beta-lapachone Against Hl-60: A Redox-dependent Mechanism

In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO 2) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF 4) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO 2. QPhNO 2 caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO 2 treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry. © 2012 Elsevier Ltd.264585594Asche, C., Antitumour quinones (2005) Mini-Rev. Med. Chem., 5, pp. 449-467Ausubel, F.M., Brent, R., Kingston, R.E., Moore, D.D., Seidmann, J.G., Struhl, K., (1990) Current Protocols in Molecular Biology, 2. , John Wiley & Sons, Inc., New YorkBova, M.P., Mattson, M.N., Vasile, S., Tam, D., Holsinge, L., Bremer, M., Hui, T., Fukuto, J.M., The oxidative mechanism of action of ortho-quinone inhibitors of protein-tyrosine phosphatase alpha is mediated by hydrogen peroxide (2004) Arch. Biochem. Biophys., 429, pp. 30-41Brett, A.M.O., Goulart, M.O.F., de Abreu, F.C., Reduction of lapachones and their reaction with L-cysteine and mercaptoethanol on glassy carbon electrodes (2002) Bioelectrochemistry, 56, pp. 53-55Cavalcanti, J.C.M., Oliveira, N.V., de Moura, M.A.B.F., Chaves, J.B., Alves, R.J., de Abreu, F.C., Goulart, M.O.F., Effect of the leaving group on the electrodic reduction mechanism of anti-Helicobacter pylori metronidazole derivatives, in aprotic and protic media (2004) Bioelectrochemistry, 63, pp. 353-357Cavalcanti, B.C., Barros, F.W.A., Cabral, I.O., Ferreira, J.R.O., Magalhães, H.I.F., Júnior, H.V.N., da Silva Júnior, E.N., Pessoa, C., Preclinical genotoxicology of nor-β-lapachone in human cultured lymphocytes and Chinese hamster lung fibroblasts (2011) Chem. Res. Toxicol., 24, pp. 1560-1574da Silva Júnior, E.N., de Souza, M.C.B.V., Pinto, A.V., Pinto, M.C.F.R., Goulart, M.O.F., Barros, F.W.A., Pessoa, C., Ferreira, V.F., Synthesis and potent antitumor activity of new arylamino derivatives of nor-β-lapachone and nor-α-lapachone (2007) Bioorg. Med. Chem., 15, pp. 7035-7041da Silva Júnior, E.N., Moura, M.A.B.F., Pinto, A.V., Pinto, M.C.F.R., de Souza, M.C.B.V., Araújo, A.J., Pessoa, C., Goulart, M.O.F., Cytotoxic, trypanocidal activities and physicochemical parameters of nor-β-lapachone-based 1,2,3-triazoles (2009) J. Braz. Chem. Soc., 20, pp. 635-643da Silva Júnior, E.N., de Deus, C.F., Martins, J.B.L., Lima, A.B., Cavalcanti, B.C., Pessoa, C., Costa-Lotufo, L.V., Pinto, A.V., 3-Arylamino and 3-alkoxy-nor-β-lapachone derivatives: synthesis and cytotoxicity against cancer cell lines (2010) J. Med. Chem., 53, pp. 504-508Darzynkiewicz, Z., Bruno, S., Del Bino, G., Gorczyca, M., Hotz, M.A., Lassota, P., Traganos, F., Features of apoptotic cells measured by flow cytometry (1992) Cytometry, 13, pp. 795-808de Abreu, F.C., Ferraz, P.A.M., Goulart, M.O.F., Some applications of electrochemistry in biomedical chemistry. Emphasis on the correlation of electrochemical and bioactive properties (2002) J. Braz. Chem. Soc., 13, pp. 19-35de Abreu, F.C., Goulart, M.O.F., Brett, A.M.O., Reduction of lapachones in aqueous media at a glassy carbon electrode (2002) Electroanalysis, 14, pp. 29-34de Abreu, F.C., Ferreira, D.C.M., Goulart, M.O.F., Buriez, O., Amatore, C., Electrochemical activation of beta-lapachone in beta-cyclodextrin inclusion complexes and reactivity of its reduced form towards oxygen in aqueous solutions (2007) J. Electroanal. Chem., 608, pp. 125-132de Abreu, F.C., de Paula, F.S., Ferreira, D.C.M., Nascimento, V.B., Santos, A.M.C., Santoro, M., Salas, C.E., Goulart, M.O.F., The application of DNA-biosensors and differential scanning calorimetry to the study of the DNA-binding agent berenil (2008) Sensors, 8, pp. 1519-1538de Souza, A.A., de Moura, M.A.B.F., de Abreu, F.C., Goulart, M.O.F., da Silva Júnior, E.N., Pinto, A.V., Ferreira, V.F., Squella, J.A., Electrochemical study, on mercury, of a meta-nitroarylamine derivative of nor-β-lapachone, an antitumor and trypanocidal compound (2010) Quim. Nova, 33, pp. 2075-2079Diculescu, V.C., Paquim, A.M.C., Brett, A.M.O., Electrochemical DNA sensors for detection of DNA damage (2005) Sensors, 5, pp. 377-393Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., Nagata, S., A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD (1998) Nature, 391, pp. 43-50Eskes, R., Desagher, S., Antonsson, B., Martinou, J.C., Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane (2000) Mol. Cell Biol., 20, pp. 929-935Ferreira, D.C.M., Tapsoba, I., Arbault, S., Bouret, Y., Alexandre Moreira, M.S., Pinto, A.V., Goulart, M.O.F., Amatore, C., Ex vivo activities of β-lapachone and α-lapachone on macrophages: a quantitative pharmacological analysis based on amperometric monitoring of oxidative bursts by single cells (2009) ChemBioChem, 10, pp. 528-538Foye, W.O., (1995) Cancer Chemotherapeutic Agents, , American Chemical Society, Washington, D.CGoulart, M.O.F., Ossowski, T., Pipka, P., Liwo, A., Electrochemical study of oxygen interaction with lapachol and its radical anions (2003) Bioelectrochemistry, 59, pp. 85-87Goulart, M.O.F., Lima, N.M.F., Santana, A.E.G., Ferraz, P.A.L., Cavalcanti, J.C.M., Liwo, A., Falkowsky, P., Ossowsky, T., Electrochemical studies of isolapachol with emphasis on oxygen interaction with its radical anions (2004) J. Electroanal. Chem., 566, pp. 25-29Goulart, M.O.F., de Souza, A.A., de Abreu, F.C., de Paula, F.S., Sales, E.M., Almeida, W.P., Buriez, O., Amatore, C., Electrochemical study of methyl 2-[p-nitrophenyl(hydroxy)methyl]acrylate (2007) J. Electrochem. Soc., 154, pp. 121-129Gupta, D., Podar, K., Tai, Y.T., Lin, B., Hideshima, T., Akiyama, M., LeBlanc, R., Anderson, K.C., Beta-lapachone, a novel plant product, overcomes drug resistance in human multiple myeloma cells (2002) Exp. Hematol., 30, pp. 711-720Hanahan, D., Weinberg, R.A., The hallmarks of cancer (2000) Cell, 100, pp. 57-70Hernández, D.M., de Moura, M.A.B.F., Valencia, D.P., González, F.J., González, I., de Abreu, F.C., da Silva Júnior, E.N., Frontana, C., Inner reorganization during the radical-biradical transition in a nor-beta-lapachone derivative possessing two redox centers (2008) Org. Biomol. Chem., 6, pp. 3414-3420Hileman, E.O., Liu, J., Albitar, M., Keateng, M.J., Huang, P., Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity (2004) Cancer Chemother. Pharmacol., 53, pp. 209-219Hillard, E.A., de Abreu, F.C., Ferreira, D.C.M., Jaouen, G., Goulart, M.O.F., Amatore, C., Electrochemical parameters and techniques in drug development, with an emphasis on quinones and related compounds (2008) Chem. Commun., pp. 2612-2628Kerr, J.F.R., Wyllie, A.H., Currie, A.R., Apoptosis-Basic biological phenomenon with wide-ranging implications in tissue kinetics (1972) Brit. J. Cancer, 26, pp. 239-257Lebel, C.P., Ischiropoulos, H., Bondy, S.C., Evaluation of the probe 2',7'-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress (1992) Chem. Res. Toxicol., 5, pp. 227-231Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S., Wang, X., Cytochrome C and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade (1997) Cell, 91, pp. 479-489Melino, G., The Sirens' song (2001) Nature, 412, p. 23Mizutani, H., Tada-Oikawa, S., Hiraku, Y., Oikawa, S., Kojima, M., Kawanishi, S., Mechanism of apoptosis induced by a new topoisomerase inhibitor through the generation of hydrogen peroxide (2002) J. Biol. Chem., 277, pp. 30684-30689Montenegro, R.C., Araújo, A.J., Molina, M.T., Marinho-Filho, J.D.B., Rocha, D.D., Lopez-Montero, E., Goulart, M.O.F., Costa-Lotufo, L.V., Cytotoxic activity of naphthoquinones with special emphasis on juglone and its 5-O-methyl derivative (2010) Chem. Biol. Interact., 184, pp. 439-448Mosmann, T., Rapid colorimetric assay for cellular growth and survival application to proliferation and cyto-toxicity assays (1983) J. Immunol. Methods, 65, pp. 55-63Okada, H., Mak, T.W., Pathways of apoptotic and non-apoptotic death in tumour cells (2004) Nat. Rev. Cancer, 4, pp. 592-603Oliveira-Brett, A.M., Vivan, M., Fernandes, I.R., Piedade, J.A.P., Electrochemical detection of in situ adriamycin oxidative damage to DNA (2002) Talanta, 56, pp. 959-970Ossowski, T., Pipka, P., Liwo, A., Jeziorek, D., Electrochemical and UV-spectrophotometric study of oxygen and superoxide anion radical interaction with anthraquinone derivatives and their radical anions (2000) Electrochim. Acta, 45, pp. 3581-3587Ozben, T., Oxidative stress and apoptosis: impact on cancer therapy (2007) J. Pharm. Sci., 96, pp. 2181-2196Piedade, J.A.P., Fernandez, I.R., Brett, A.M.O., Electrochemical sensing of DNA-adriamycin interactions (2002) Bioelectrochemistry, 56, pp. 81-83Planchon, S.M., Wuerzberger, S., Frydman, B., Witiak, D.T., Hutson, P., Church, D.R., Wilding, G., Boothman, D.A., β-Lapachone-mediated apoptosis in human promyelocytic leukemia (HL-60) and human prostate cancer cells: a p53-independent response (1995) Cancer Res., 55, pp. 3706-3711Planchon, S.M., Wuerzberger-Davis, S.M., Pink, J.J., Robertson, K.A., Bornmann, W.G., Boothman, D.A., Bcl-2 protects against beta-lapachone-mediated caspase 3 activation and apoptosis in human myeloid leukemia (HL-60) cells (1999) Oncol Rep., 6, pp. 485-492Rauf, S., Gooding, J.J., Akhtar, K., Ghauri, M.A., Rahman, M., Anwar, M.A., Khalid, A.M., Electrochemical approach of anticancer drugs - DNA interaction (2005) J. Pharm. Biomed. Anal., 37, pp. 205-217Singh, N.P., McCoy, M.T., Tice, R.R., Schneider, E.L., A simple technique for quantitation of low-levels of DNA damage in individual cells (1988) Exp. Cell Res., 175, pp. 184-191Wang, J., Ozsoz, M., Cai, X.H., Rivas, G., Shiraishi, H., Grant, D.H., Chicharro, M., Palecek, E., Interactions of antitumor drug daunomycin with DNA in solution and at the surface (1998) Bioelectrochem. Bioenerg., 45 (1998), pp. 33-40Zafarullaha, M., Lia, W.Q., Sylvestera, J., Ahmad, M., Molecular mechanisms of N-acetylcysteine actions (2003) Cell. Mol. Life Sci., 60, pp. 6-20Ziegler, U., Groscurth, P., Morphological features of cell death (2004) News Physiol. Sci., 19, pp. 124-12

Efeitos de rações com níveis crescentes de cana-de-açúcar em substituição à silagem de milho sobre a população de protozoários ciliados no rúmen de ovinos Effects of diets with increasing levels of sugar cane in substitution of corn silage on rumen population ciliate protozoa in sheep

Oito ovinos machos com fístulas ruminais foram delineados em dois quadrados latinos, em quatro períodos de 35 dias cada e quatro tratamentos, compreendendo níveis crescentes de cana-de-açúcar (CA) em substituição à silagem de milho (SM): A) 100% SM; B) 67% SM e 33% CA; C) 33% SM e 67% CA; e D 100% CA, para avaliação da população de protozoários ciliados no rúmen. As concentrações totais de protozoários ciliados no rúmen e de Entodinium diminuíram e os valores de pH do conteúdo ruminal aumentaram linearmente com o incremento das quantidades de cana-de-açúcar na ração. Não houve diferenças entre tratamentos para o volume ruminal e a taxa de passagem da fase líquida do rúmen.<br>Eight rumen fistulated rams were delineated in two Latin Squares in four periods of 35 days each and four treatments consisted of increasing levels of sugar cane (SC) in substitution to the corn silage (CS): A) 100% CS, B) 67% CS and 33% SC, C) 33% CS and 67% SC and D) 100% SC, to evaluate the population of ciliate protozoa in the rumen. The total concentrations of rumen ciliate protozoa and of Entodinium decreased and the values of pH of the ruminal content increased linearly as dietary sugar cane levels increased. No differences between treatments were observed for the rumen volume and the rumen liquid turnover rate