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151.
Bruno J. Neves Rodolpho C. Braga José C. B. Bezerra Pedro V. L. Cravo Carolina H. Andrade 《PLoS neglected tropical diseases》2015,9(1)
Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes. 相似文献
152.
Selective Cytotoxicity of 1,3,4-Thiadiazolium Mesoionic Derivatives on Hepatocarcinoma Cells (HepG2)
Gustavo Jabor Gozzi Amanda do Rocio Andrade Pires Glaucio Valdameri Maria Eliane Merlin Rocha Glaucia Regina Martinez Guilhermina Rodrigues Noleto Alexandra Acco Carlos Eduardo Alves de Souza Aurea Echevarria Camilla Moretto dos Reis Attilio Di Pietro Sílvia Maria Suter Correia Cadena 《PloS one》2015,10(6)
In this work, we evaluated the cytotoxicity of mesoionic 4-phenyl-5-(2-Y, 4-X or 4-X-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride derivatives (MI-J: X=OH, Y=H; MI-D: X=NO2, Y=H; MI-4F: X=F, Y=H; MI-2,4diF: X=Y=F) on human hepatocellular carcinoma (HepG2), and non-tumor cells (rat hepatocytes) for comparison. MI-J, M-4F and MI-2,4diF reduced HepG2 viability by ~ 50% at 25 μM after 24-h treatment, whereas MI-D required a 50 μM concentration, as shown by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The cytotoxicity was confirmed with lactate dehydrogenase assay, of which activity was increased by 55, 24 and 16% for MI-J, MI-4F and MI-2,4diF respectively (at 25 μM after 24 h). To identify the death pathway related to cytotoxicity, the HepG2 cells treated by mesoionic compounds were labeled with both annexin V and PI, and analyzed by flow cytometry. All compounds increased the number of doubly-stained cells at 25 μM after 24 h: by 76% for MI-J, 25% for MI-4F and MI-2,4diF, and 11% for MI-D. It was also verified that increased DNA fragmentation occurred upon MI-J, MI-4F and MI-2,4diF treatments (by 12%, 9% and 8%, respectively, at 25 μM after 24 h). These compounds were only weakly, or not at all, transported by the main multidrug transporters, P-glycoprotein, ABCG2 and MRP1, and were able to slightly inhibit their drug-transport activity. It may be concluded that 1,3,4-thiadiazolium compounds, especially the hydroxy derivative MI-J, constitute promising candidates for future investigations on in-vivo treatment of hepatocellular carcinoma. 相似文献
153.
154.
Lucas Martins França Larissa Nara Costa Freitas Vinicyus Teles Chagas Caio Fernando Ferreira Coêlho Wermerson Assunção Barroso Graciomar Conceição Costa Lucilene Amorim Silva Victor Debbas Francisco Rafael Martins Laurindo Antonio Marcus de Andrade Paes 《Biochemical and biophysical research communications》2014
Non-alcoholic fatty liver disease (NAFLD) is intimately associated with insulin resistance and hypertriglyceridemia, whereas many of the mechanisms underlying this association are still poorly understood. In the present study, we investigated the relationship between microsomal triglyceride transfer protein (MTP) and markers of endoplasmic reticulum (ER) stress in the liver of rats subjected to neonatal monosodium l-glutamate (MSG)-induced obesity. At age 120 days old, the MSG-obese animals exhibited hyperglycemia, hypertriglyceridemia, insulin resistance, and liver steatosis, while the control (CTR) group did not. Analysis using fast protein liquid chromatography of the serum lipoproteins revealed that the triacylglycerol content of the very low-density lipoprotein (VLDL) particles was twice as high in the MSG animals compared with the CTR animals. The expression of ER stress markers, GRP76 and GRP94, was increased in the MSG rats, promoting a higher expression of X-box binding protein 1 (XBP-1), protein disulfide isomerase (PDI), and MTP. As the XBP-1/PDI/MTP axis has been suggested to represent a significant lipogenic mechanism in the liver response to ER stress, our data indicate that hypertriglyceridemia and liver steatosis occurring in the MSG rats are associated with increased MTP expression. 相似文献
155.
D. C. Zied M. T. A. Minhoni J. Kopytowski-Filho M. C. N. Andrade 《World journal of microbiology & biotechnology》2010,26(10):1857-1863
To investigate the yield and precocity of Agaricus blazei using to different casing layers and cultivation environments, five casing layers were prepared with soil (different textures),
wood charcoal, and calcitic lime. After colonization, the composts were placed in two growing rooms (controlled environment
and plastic greenhouse) and cased. The cycle was 120 days. Yield and precocity data were evaluated in a factorial combination
(5 soil types ×2 cultivation environments) and 8 replications. The results showed low yields when cultivated in a controlled
room (1.55 kg of mushrooms per box) and yield values of different soils ranged between 1.61 and 1.88 kg of mushrooms per box.
The precocity values of the different soils and environments ranged between 62 and 51% in the first 50 days of production.
The various soil types did not differ statistically for yield values (kg) and the plastic greenhouse provided higher yields.
The texture of the different soils and environment directly influenced precocity in A. blazei yield. 相似文献
156.
Matthew G. Stanton Jed Hubbs David Sloman Christopher Hamblett Paula Andrade Minilik Angagaw Grace Bi Regina M. Black Jamie Crispino Jonathan C. Cruz Eric Fan Georgia Farris Bethany L. Hughes Candia M. Kenific Richard E. Middleton George Nikov Peter Sajonz Sanjiv Shah Nirah Shomer Alexander A. Szewczak Benito Munoz 《Bioorganic & medicinal chemistry letters》2010,20(2):755-758
We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor®. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Aβ42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250 mg/kg per day, AUC0–24 = 2100 μM h) did not exhibit Notch-related effects. 相似文献
157.
Fernando Berton Zanchi Rafael Andrade Caceres Rodrigo Guerino Stabeli Walter Filgueira de Azevedo Jr. 《Journal of molecular modeling》2010,16(3):543-550
Purine nucleoside phosphorylase (PNP) (EC.2.4.2.1) is an enzyme that catalyzes the cleavage of N-ribosidic bonds of the purine
ribonucleosides and 2-deoxyribonucleosides in the presence of inorganic orthophosphate as a second substrate. This enzyme
is involved in purine-salvage pathway and has been proposed as a promising target for design and development of antimalarial
and antibacterial drugs. Recent elucidation of the three-dimensional structure of PNP by X-ray protein crystallography left
open the possibility of structure-based virtual screening initiatives in combination with molecular dynamics simulations focused
on identification of potential new antimalarial drugs. Most of the previously published molecular dynamics simulations of
PNP were carried out on human PNP, a trimeric PNP. The present article describes for the first time molecular dynamics simulations
of hexameric PNP from Plasmodium falciparum (PfPNP). Two systems were simulated in the present work, PfPNP in ligand free form, and in complex with immucillin and sulfate.
Based on the dynamical behavior of both systems the main results related to structural stability and protein-drug interactions
are discussed.
相似文献
158.
Saraiva L Andrade Filho JD Silva Sde O Andrade AS Melo MN 《Memórias do Instituto Oswaldo Cruz》2010,105(8):1033-1039
Over the last 20 years, there has been an increase in the number of leishmaniasis cases in Brazil. Belo Horizonte (BH) is one of the most highly populated Brazilian cities that is affected by visceral leishmaniasis (VL). The health services in BH are coordinated by a central nucleus that is subdivided into nine sanitary districts. Historically, the highest level of human VL cases was found in the northeast sanitary district (NSD). The objective of our study was to detect Leishmania infection in the phlebotomine sand flies collected in the NSD by dissection and molecular approaches. Following the occurrence of human VL cases in 2005, entomological captures were performed from July 2006-June 2007. Out of the 245 sand flies dissected, only three Lutzomyia longipalpis spp contained flagellates. The female sand flies were grouped into 120 pools according to date, collection site and species, with approximately 10 individual sand flies in each pool. Subsquently, the DNA was extracted and Leishmania spp and other parasites were detected and identified by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorfism. Leishmania infantum was present in at least 19% of the Lu. longipalpis collected, in 3.8% of the Nyssomiya whitmani collected, in 33.3% of the Evandromiya termitophila collected and in 14.3% of the Nyssomiya intermedia collected. When the females of the cortelezzii complex were compared with each other, 3.2% of the females were infected with Leishmania braziliensis, whereas 3.2% of the females were infected with trypanosomatids. 相似文献
159.
Machado AS Andrade GM Januário JN Fernandes MD Carneiro AC Carneiro M Carellos EV Romanelli RM Vasconcelos-Santos DV Vitor RW 《Memórias do Instituto Oswaldo Cruz》2010,105(6):757-761
The aim of this study was to evaluate the utility of western blot (WB) analysis as a diagnostic tool for congenital toxoplasmosis in 215 newborn infants. The children were submitted to clinical examinations to assess macular, neurological and hearing signals. The WB results obtained were compared to the persistence of IgG antibodies at the end of 12 months, which is regarded as the "gold standard" diagnosis of congenital toxoplasmosis. Association between the WB results and the clinical signs presented by the infants was also assessed. Of the 215 children, 177 had a confirmed congenital toxoplasmosis diagnosis and 38 were uninfected. IgG-WB showed a sensitivity of 73.5% and a specificity of 97.4%. IgM-WB showed a sensitivity of 54.8% and a specificity of 94.7%. The IgG-WB and IgM-WB combination increased the sensitivity to 86.5%. The IgM-WB-positive children had a 1.4-fold greater risk of presenting active macular lesions than did those that were IgM-WB-negative. This study showed that the WB assay is a useful tool to confirm a diagnosis of congenital toxoplasmosis and that the IgM-WB-positive results can indicate active macular lesions in newborn infants. 相似文献
160.
Mirna Valdez-Hernández José Luis Andrade Paula C. Jackson Mario Rebolledo-Vieyra 《Plant and Soil》2010,329(1-2):155-171
In order to relate phenological responses of trees to environmental variables we recorded the phenological patterns and select morphological and physiological traits (wood density and water potentials) of five tree species (Acacia gaumeri, Apoplanesia paniculata, Bursera simaruba, Gymnopodium floribundum, and Diospyros cuneata) in the tropical dry deciduous forest of the National Park of Dzibilchaltún, Yucatan, Mexico, over a period of 2 years (2004 and 2005). We chose two sites: one close to a permanent water source, locally known as ‘cenote’ (the CC site, ground water table was found at 2 m) and the other far from the cenote (FC site ground water table was at a depth of 10 m). Sites mainly differed in soil depth (FC site having greater soil depth) and soil nutrient characteristics (FC site more potassium, CC site more phosphorous). Our results indicated significant differences in phenology within species between sites and years, with leaf, flower and fruit production tending to be higher at the CC site and in the year 2004. Wood density and xylem water potentials were negatively related to each other, and midday water potentials were higher at the CC site. Differences in phenology found among years suggest that the timing of rainfall as well as the duration of periods without rain may play a more important role in phenology than total annual precipitation. Also differences inter-sites suggest a strong effect of site on tree phenology. Proximity to superficial bodies of water, such as cenotes, coupled with a greater concentration of available phosphorus in the soil may modify the effect of drought in this tropical dry deciduous forest. 相似文献