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https://www.readbyqxmd.com/read/28350440/identification-of-trypanosoma-brucei-adometdc-inhibitors-using-a-high-throughput-mass-spectrometry-based-assay
#1
Oleg A Volkov, Casey C Cosner, Anthony J Brockway, Martin Kramer, Michael Booker, Shihua Zhong, Ariel Ketcherside, Shuguang Wei, Jamie Longgood, Melissa K McCoy, Thomas E Richardson, Stephen A Wring, Michael Peel, Jeffrey D Klinger, Bruce A Posner, Jef K De Brabander, Margaret A Phillips
Human African trypanosomiasis (HAT) is a fatal infectious disease caused by the eukaryotic pathogen Trypanosoma brucei. Available treatments are difficult to administer and have significant safety issues. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the parasite polyamine biosynthetic pathway. Previous attempts to develop TbAdoMetDC inhibitors into anti-HAT therapies failed due to poor brain exposure. Here, we describe a large screening campaign of two small-molecule libraries (~400,000 compounds) employing a new high-throughput (~7 s per sample) mass spectrometry-based assay for AdoMetDC activity...
March 28, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28344657/well-positioned-nucleosomes-punctuate-polycistronic-pol-ii-transcription-units-and-flank-silent-vsg-gene-arrays-in-trypanosoma-brucei
#2
Johannes Petrus Maree, Megan Lindsay Povelones, David Johannes Clark, Gloria Rudenko, Hugh-George Patterton
BACKGROUND: The compaction of DNA in chromatin in eukaryotes allowed the expansion of genome size and coincided with significant evolutionary diversification. However, chromatin generally represses DNA function, and mechanisms coevolved to regulate chromatin structure and its impact on DNA. This included the selection of specific nucleosome positions to modulate accessibility to the DNA molecule. Trypanosoma brucei, a member of the Excavates supergroup, falls in an ancient evolutionary branch of eukaryotes and provides valuable insight into the organization of chromatin in early genomes...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28341394/serum-biochemical-profile-and-molecular-detection-of-pathogens-in-semen-of-infertile-male-dromedary-camels-camelus-dromedarius
#3
Khaled A Al-Busadah, Sabry M El-Bahr, Abdelmalik I Khalafalla
Detection of pathogens in the semen of camels has not been completely elucidated. Therefore, the current study aimed to determine the association of some economically important pathogens with infertility in 94 male infertile camels through molecular detection and estimation of selected biochemical parameters in serum of these animals compared with a control non infected fertile animals (n=40). PCR analysis of semen samples of infertile camels indicated that, four potential pathogens namely Mycoplasma spp., Leptospira spp...
March 9, 2017: Animal Reproduction Science
https://www.readbyqxmd.com/read/28338335/stress-induced-protein-s-glutathionylation-and-s-trypanothionylation-in-african-trypanosomes-a-quantitative-redox-proteome-and-thiol-analysis
#4
Kathrin Ulrich, Caroline Finkenzeller, Sabine Merker, Federico Rojas, Keith Matthews, Thomas Ruppert, R Luise Krauth-Siegel
AIMS: Trypanosomatids have a unique trypanothione-based thiol redox metabolism. The parasite-specific dithiol is synthesized from glutathione and spermidine, with glutathionylspermidine as intermediate catalyzed by trypanothione synthetase. In this study, we address the oxidative stress response of African trypanosomes with special focus on putative protein S-thiolation. RESULTS: Challenging bloodstream Trypanosoma brucei with diamide, H2O2 or hypochlorite results in distinct levels of reversible overall protein S-thiolation...
March 24, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28337329/antiparasitic-lead-discovery-toward-optimization-of-a-chemotype-with-activity-against-multiple-protozoan-parasites
#5
William Devine, Sarah M Thomas, Jessey Erath, Kelly A Bachovchin, Patricia J Lee, Susan E Leed, Ana Rodriguez, Richard J Sciotti, Kojo Mensa-Wilmot, Michael P Pollastri
Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis present a significant burden across the developing world. Existing therapeutics for these protozoal neglected tropical diseases suffer from severe side effects and toxicity. Previously, NEU-1045 (3) was identified as a promising lead with cross-pathogen activity, though it possessed poor physicochemical properties. We have designed a library of analogues with improved calculated physicochemical properties built on the quinoline scaffold of 3 incorporating small, polar aminoheterocycles in place of the 4-(3-fluorobenzyloxy)aniline substituent...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28336470/bioassay-guided-isolation-of-active-principles-from-nigerian-medicinal-plants-identifies-new-trypanocides-with-low-toxicity-and-no-cross-resistance-to-diamidines-and-arsenicals
#6
Godwin Unekwuojo Ebiloma, John Ogbaji Igoli, Evangelos Katsoulis, Anne-Marie Donachie, Anthonius Eze, Alexander Ian Gray, Harry P de Koning
ETHNOPHARMACOLOGICAL RELEVANCE: Leaves from the plant species studied herein are traditionally used in northern Nigeria against various protozoan infections. However, none of these herbal preparations have been standardized, nor have their toxicity to mammalian cells been investigated. In search of improved and non-toxic active antiprotozoal principles that are not cross-resistant with current anti-parasitics, we here report the results of the in vitro screening of extracts from seven selected medicinal plant species (Centrosema pubescens, Moringa oleifera, Tridax procumbens, Polyalthia longifolia, Newbouldia laevis, Eucalyptus maculate, Jathropha tanjorensis), used traditionally to treat kinetoplastid infections in Nigeria, and the isolation of their bioactive principles...
March 20, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28334836/trypanosoma-brucei-rap1-maintains-telomere-and-subtelomere-integrity-by-suppressing-terra-and-telomeric-rna-dna-hybrids
#7
Vishal Nanavaty, Ranjodh Sandhu, Sanaa E Jehi, Unnati M Pandya, Bibo Li
Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, thereby evading the host's immune response. VSGs are monoallelically expressed from subtelomeric expression sites (ESs), and VSG switching exploits subtelomere plasticity. However, subtelomere integrity is essential for T. brucei viability. The telomeric transcript, TERRA, was detected in T. brucei previously. We now show that the active ES-adjacent telomere is transcribed. We find that TbRAP1, a telomere protein essential for VSG silencing, suppresses VSG gene conversion-mediated switching...
March 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334821/in-vivo-cleavage-specificity-of-trypanosoma-brucei-editosome-endonucleases
#8
Jason Carnes, Suzanne McDermott, Atashi Anupama, Brian G Oliver, D Noah Sather, Kenneth Stuart
RNA editing is an essential post-transcriptional process that creates functional mitochondrial mRNAs in Kinetoplastids. Multiprotein editosomes catalyze pre-mRNA cleavage, uridine (U) insertion or deletion, and ligation as specified by guide RNAs. Three functionally and compositionally distinct editosomes differ by the mutually exclusive presence of the KREN1, KREN2 or KREN3 endonuclease and their associated partner proteins. Because endonuclease cleavage is a likely point of regulation for RNA editing, we elucidated endonuclease specificity in vivo...
February 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334017/genome-wide-rnai-selection-identifies-a-regulator-of-transmission-stage-enriched-gene-families-and-cell-type-differentiation-in-trypanosoma-brucei
#9
Eva Rico, Alasdair Ivens, Lucy Glover, David Horn, Keith R Matthews
Trypanosoma brucei, causing African sleeping-sickness, exploits quorum-sensing (QS) to generate the 'stumpy forms' necessary for the parasite's transmission to tsetse-flies. These quiescent cells are generated by differentiation in the bloodstream from proliferative slender forms. Using genome-wide RNAi selection we screened for repressors of transmission stage-enriched mRNAs in slender forms, using the stumpy-elevated ESAG9 transcript as a model. This identified REG9.1, whose RNAi-silencing alleviated ESAG9 repression in slender forms and tsetse-midgut procyclic forms...
March 23, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28333926/performance-of-tci-tcvi-tcii-chagas-flow-ate-igg2a-for-universal-and-genotype-specific-serodiagnosis-of-trypanosoma-cruzi-infection
#10
Glaucia Diniz Alessio, Fernanda Fortes de Araújo, Denise Fonseca Côrtes, Policarpo Ademar Sales Júnior, Daniela Cristina Lima, Matheus de Souza Gomes, Laurence Rodrigues do Amaral, Marcelo Antônio Pascoal Xavier, Andréa Teixeira-Carvalho, Olindo Assis Martins-Filho, Marta de Lana
Distinct Trypanosoma cruzi genotypes have been considered relevant for patient management and therapeutic response Chagas disease. However, typing strategies for genotype-specific serodiagnosis of Chagas disease are still unavailable and requires standardization for practical application. In this study, an innovative TcI/TcVI/TcII Chagas Flow ATE-IgG2a technique was developed with applicability for universal and genotype-specific diagnosis of T. cruzi infection. For this purpose, the reactivity of serum samples (percentage of positive fluorescent parasites-PPFP) obtained from mice chronically infected with TcI/Colombiana, TcVI/CL or TcII/Y strain as well as non-infected controls were determined using amastigote-AMA, trypomastigote-TRYPO and epimastigote-EPI in parallel batches of TcI, TcVI and TcII target antigens...
March 23, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28333923/interdisciplinary-approach-at-the-primary-healthcare-level-for-bolivian-immigrants-with-chagas-disease-in-the-city-of-s%C3%A3-o-paulo
#11
Maria Aparecida Shikanai Yasuda, Camila Gonçalves Sátolo, Noemia Barbosa Carvalho, Magda Maya Atala, Rosario Quiroga Ferrufino, Ruth Moreira Leite, Célia Regina Furucho, Expedito Luna, Rubens Antonio Silva, Marcia Hage, Caroline Medeji Ramos de Oliveira, Felipe Delatorre Busser, Vera Lucia Teixeira de Freitas, Dalva Marli Valerio Wanderley, Luzia Martinelli, Sonia Regina Almeida, Pedro Albajar Viñas, Nivaldo Carneiro
BACKGROUND/METHODS: In a pioneering cross-sectional study among Bolivian immigrants in the city of São Paulo, Brazil, the epidemiological profile, clinical manifestations and morbidity of Chagas disease were described. The feasibility of the management of Chagas disease at primary healthcare clinics using a biomedical and psychosocial interdisciplinary approach was also tested. Previously, a Trypanosoma cruzi (T. cruzi) infection rate of 4.4% among 633 immigrants was reported. The samples were screened using two commercial enzyme-linked immunoassay (ELISA) tests generated with epimastigote antigens, and those with discrepant or seropositive results were analyzed by confirmatory tests: indirect immunofluorescence (IFI), TESA-blot and a commercial recombinant ELISA...
March 23, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28333400/an-improved-model-of-the-trypanosoma-brucei-ctp-synthetase-glutaminase-domain-acivicin-complex
#12
Juliana Oliveira de Souza, Alice Dawson, William Nigel Hunter
The natural product acivicin inhibits the glutaminase activity of CTP synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1 Å resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the Protein Data Bank and provides a template for structure-based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model...
March 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28329730/synthesis-of-novel-quinoline-based-4-5-dihydro-1h-pyrazoles-as-potential-anticancer-antifungal-antibacterial-and-antiprotozoal-agents
#13
Jonathan Ramírez-Prada, Sara M Robledo, Iván D Vélez, María Del Pilar Crespo, Jairo Quiroga, Rodrigo Abonia, Alba Montoya, Laura Svetaz, Susana Zacchino, Braulio Insuasty
A new series of N-substituted 2-pyrazolines 9a-f, 10a-f, 11a-f, 12a-f and 13a-f were obtained from the cyclocondensation reaction of [(7-chloroquinolin-4-yl)amino]chalcones 8a-f with hydrazine hydrate and its derivatives. Fourteen of the synthesized compounds including the starting chalcones were selected by US National Cancer Institute (NCI) for testing their anticancer activity against 60 different human cancer cell lines, with the most important GI50 values ranging from 0.28 to 11.7 μM (0.13-6.05 μg/mL) and LC50 values ranging from 2...
March 16, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28328108/ex-vivo-infection-of-human-placental-chorionic-villi-explants-with-trypanosoma-cruzi-and-toxoplasma-gondii-induces-different-toll-like-receptor-expression-and-cytokine-chemokine-profiles
#14
Christian Castillo, Lorena Muñoz, Ileana Carrillo, Ana Liempi, Christian Gallardo, Norbel Galanti, Juan Diego Maya, Ulrike Kemmerling
PROBLEM: Trypanosoma cruzi and Toxoplasma gondii present, respectively, low and high congenital transmission rates. The placenta as an immune regulatory organ expresses TLRs, leading to the secretion of cytokines. Both parasites are recognized by TLR-2, TLR-4, and TLR-9. Here, we studied if the parasites induce differences in TLR protein expression, cytokine profiles, and whether receptor inhibition is related to parasite infection. METHOD OF STUDY: Placental tissue explants were infected ex vivo with each parasite, TLRs protein expression, cytokine profile and parasite infection were determined by Western blotting, ELISA and qPCR...
March 22, 2017: American Journal of Reproductive Immunology: AJRI
https://www.readbyqxmd.com/read/28327801/analysis-of-the-seroprevalence-of-and-factors-associated-with-chagas-disease-in-an-endemic-area-in-northeastern-brazil
#15
Erlane Chaves Freitas, Maria de Fátima Oliveira, Arduina Sofia Ortet de Barros Vasconcelos, José Damião da Silva, Carlos Eduardo Menezes Viana, Kátia Cristina Morais Soares Gomes, Luciano Pamplona de Góes Cavalcanti
INTRODUCTION: Chagas disease (CD) is currently considered a neglected disease; hence, identifying the factors associated with its high prevalence is essential. This study aimed to identify the seroprevalence of and the possible factors associated with CD in inhabitants of the City of Limoeiro do Norte, Northeastern Brazil. METHODS: Between April and November 2013, blood collection was conducted and a semi-structured questionnaire was administered. Blood samples that showed positive or possible serology for anti-Trypanosoma cruzi antibodies based on indirect immunofluorescence, hemagglutination indirect, and an enzyme-linked immunosorbent assay were analyzed...
January 2017: Revista da Sociedade Brasileira de Medicina Tropical
https://www.readbyqxmd.com/read/28327800/trypanosoma-cruzi-i-genotype-among-isolates-from-patients-with-chronic-chagas-disease-followed-at-the-evandro-chagas-national-institute-of-infectious-diseases-fiocruz-brazil
#16
Tatiana da Silva Fonseca de Oliveira, Barbara Neves Dos Santos, Tainah Silva Galdino, Alejandro Marcel Hasslocher-Moreno, Otilio Machado Pereira Bastos, Maria Auxiliadora de Sousa
INTRODUCTION: Trypanosoma cruzi is the etiologic agent of Chagas disease in humans, mainly in Latin America. Trypanosome stocks were isolated by hemoculture from patients followed at Evandro Chagas National Institute of Infectious Diseases (FIOCRUZ) and studied using different approaches. METHODS: For species and genotype identification, the stocks were analyzed by parasitological techniques, polymerase chain reaction assays targeted to specific DNA sequences, isoenzyme patterns, besides sequencing of a polymorphic locus of TcSC5D gene (one stock)...
January 2017: Revista da Sociedade Brasileira de Medicina Tropical
https://www.readbyqxmd.com/read/28327099/differential-cytokine-profiling-in-chagasic-patients-according-to-their-arrhythmogenic-status
#17
Héctor Rodríguez-Angulo, Juan Marques, Ivan Mendoza, Marco Villegas, Alfredo Mijares, Núria Gironès, Manuel Fresno
BACKGROUND: Chagas disease is caused by the protozoan Trypanosoma cruzi and is characterized by heart failure and sudden death. Identifying which factors are involved in evolution and treatment response is actually challenging. Thus, the aim of this work was to determine the Th1/Th17 (IL-6, IL-2, TNF, IL-17 and IFN-γ) and Th2 (IL-4 and IL-10) serum profile in Venezuelan Chagasic patients stratified according amiodarone treatment, hypertension and arrhythmias. METHODS: Sera from 38 chagasic patients were analyzed to determine the level of cytokines by Multiplexed Bead-Based Immunoassays...
March 21, 2017: BMC Infectious Diseases
https://www.readbyqxmd.com/read/28325373/host-parasite-relationships-and-life-histories-of-trypanosomes-in-australia
#18
C Cooper, P L Clode, C Peacock, R C A Thompson
Trypanosomes constitute a group of flagellate protozoan parasites responsible for a number of important, yet neglected, diseases in both humans and livestock. The most significantly studied include the causative agents of African sleeping sickness (Trypanosoma brucei) and Chagas disease (Trypanosoma cruzi) in humans. Much of our knowledge about trypanosome host-parasite relationships and life histories has come from these two human pathogens. Recent investigations into the diversity and life histories of wildlife trypanosomes in Australia highlight that there exists a great degree of biological and behavioural variation within and between trypanosomes...
2017: Advances in Parasitology
https://www.readbyqxmd.com/read/28325368/chagas-disease-diagnostic-applications-present-knowledge-and-future-steps
#19
V Balouz, F Agüero, C A Buscaglia
Chagas disease, caused by the protozoan Trypanosoma cruzi, is a lifelong and debilitating illness of major significance throughout Latin America and an emergent threat to global public health. Being a neglected disease, the vast majority of Chagasic patients have limited access to proper diagnosis and treatment, and there is only a marginal investment into R&D for drug and vaccine development. In this context, identification of novel biomarkers able to transcend the current limits of diagnostic methods surfaces as a main priority in Chagas disease applied research...
2017: Advances in Parasitology
https://www.readbyqxmd.com/read/28323069/minicircle-classes-heterogeneity-within-the-tciii-and-tciv-discrete-typing-units-of-trypanosoma-cruzi
#20
S Ortiz, G Osorio, A Solari
The taxon Trypanosoma cruzi, causative agent of Chagas disease, is composed of several discrete typing units (DTUs) named TcI-TcVI, and Tcbat. The history of the taxon T. cruzi is known, even though several controversial aspects remain as the relationships between TcIII and TcIV. We analyzed cloned T. cruzi stocks pertaining to the seven DTUs by filter hybridization tests of PCR amplicons from minicircle variable regions and kinetoplast DNA probes. Minicircle DNA blots from the cloned stocks and filter hybridization with one TcI, one TcII, one TcV, one TcVI, three TcIII, one TcIV from North America and one TcIV kinetoplast DNA probes from South America revealed minicircle variable region cross-reaction in some T...
March 16, 2017: Infection, Genetics and Evolution
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