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Trypanosomatids

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https://www.readbyqxmd.com/read/28939533/comparative-mapping-of-on-targets-and-off-targets-for-the-discovery-of-anti-trypanosomatid-folate-pathway-inhibitors
#1
Joanna Panecka-Hofman, Ina Pöhner, Francesca Spyrakis, Talia Zeppelin, Flavio Di Pisa, Lucia Dello Iacono, Alessio Bonucci, Antonio Quotadamo, Alberto Venturelli, Stefano Mangani, Maria Paola Costi, Rebecca C Wade
BACKGROUND: Multi-target approaches are necessary to properly analyze or modify the function of a biochemical pathway or a protein family. An example of such a problem is the repurposing of the known human anti-cancer drugs, antifolates, as selective anti-parasitic agents. This requires considering a set of experimentally validated protein targets in the folate pathway of major pathogenic trypanosomatid parasites and humans: (i) the primary parasite on-targets: pteridine reductase 1 (PTR1) (absent in humans) and bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS), (ii) the primary off-targets: human DHFR and TS, and (iii) the secondary on-target: human folate receptor β, a folate/antifolate transporter...
September 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28938001/cell-cycle-stage-specific-transcriptional-activation-of-cyclins-mediated-by-hat2-dependant-h4k10-acetylation-of-promoters-in-leishmania-donovani
#2
Udita Chandra, Aarti Yadav, Devanand Kumar, Swati Saha
Chromatin modifications affect several processes. In investigating the Leishmania donovani histone acetyltransferase HAT2, using in vitro biochemical assays and HAT2-heterozygous genomic knockout we found the constitutively nuclear HAT2 acetylated histone H4K10 in vitro and in vivo. HAT2 was essential. HAT2-depleted cells displayed growth and cell cycle defects, and poor survival in host cells. Real time PCR and DNA microarray analyses, as well as rescue experiments, revealed that downregulation of cyclins CYC4 and CYC9 were responsible for S phase and G2/M defects of HAT2-depleted cells respectively...
September 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28930584/metal-and-metalloid-containing-drugs-for-the-treatment-of-trypanosomatid-diseases
#3
Gianni Colotti, Annarita Fiorillo, Andrea Ilari
The trypanosomatid-induced diseases are considered as neglected, because the countries where they kill people are not important markets for western big pharmaceutical companies. However, recently some effort has been made to translate the use of already known drugs to neglected infectious disease. Although many metals are essential to life, many disorders affecting metal homeostasis and bioavailability are responsible for several human diseases. Metals can be toxic even at very low concentrations and semimetals are classified as toxic and dangerous for the environment...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28917755/identification-of-trypanosomatids-by-detecting-single-nucleotide-fingerprints-using-dna-analysis-by-dynamic-chemistry-with-maldi-tof
#4
María Angélica Luque-González, Mavys Tabraue-Chávez, Bárbara López-Longarela, Rosario María Sánchez-Martín, Matilde Ortiz-González, Miguel Soriano-Rodríguez, José Antonio García-Salcedo, Salvatore Pernagallo, Juan José Díaz-Mochón
Protozoan parasites of the Trypanosomatidae family can cause devastating diseases in humans and animals, such as Human African Trypanosomiasis or Sleeping Sickness, Chagas disease and Leishmaniasis. Currently, there are molecular assays for detecting parasitic infections and their post-treatment monitoring based on nucleic acid amplification, but there are still certain limitations which limit the development of assays that can detect and discriminate between parasite infections with a single test. Here, we present the development of a novel molecular assay for the rapid identification of Trypanosomatids, integrating DNA analysis by dynamic chemistry in conjunction with Matrix-Assisted Laser Desorption Ionization - Time-of-Flight Mass Spectrometry (MALDI-ToF)...
January 1, 2018: Talanta
https://www.readbyqxmd.com/read/28915239/structural-basis-for-the-high-specificity-of-a-trypanosoma-congolense-immunoassay-targeting-glycosomal-aldolase
#5
Joar Pinto, Steven Odongo, Felicity Lee, Vaiva Gaspariunaite, Serge Muyldermans, Stefan Magez, Yann G-J Sterckx
BACKGROUND: Animal African trypanosomosis (AAT) is a neglected tropical disease which imposes a heavy burden on the livestock industry in Sub-Saharan Africa. Its causative agents are Trypanosoma parasites, with T. congolense and T. vivax being responsible for the majority of the cases. Recently, we identified a Nanobody (Nb474) that was employed to develop a homologous sandwich ELISA targeting T. congolense fructose-1,6-bisphosphate aldolase (TcoALD). Despite the high sequence identity between trypanosomatid aldolases, the Nb474-based immunoassay is highly specific for T...
September 15, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28913164/haemoprotozoa-making-biological-sense-of-molecular-phylogenies
#6
REVIEW
Peter O'Donoghue
A range of protistan parasites occur in the blood of vertebrates and are transmitted by haematophagous invertebrate vectors. Some 48 genera are recognized in bood primarily on the basis of parasite morphology and host specificity; including extracellular kinetoplastids (trypanosomatids) and intracellular apicomplexa (haemogregarines, haemococcidia, haemosporidia and piroplasms). Gene sequences are available for a growing number of species and molecular phylogenies often link parasite and host or vector evolution...
December 2017: International Journal for Parasitology. Parasites and Wildlife
https://www.readbyqxmd.com/read/28911117/structure-based-domain-assignment-in-leishmania-infantum-endog-characterization-of-a-ph-dependent-regulatory-switch-and-a-c-terminal-extension-that-largely-dictates-dna-substrate-preferences
#7
Cristina Oliva, Pedro A Sánchez-Murcia, Eva Rico, Ana Bravo, Margarita Menéndez, Federico Gago, Antonio Jiménez-Ruiz
Mitochondrial endonuclease G from Leishmania infantum (LiEndoG) participates in the degradation of double-stranded DNA (dsDNA) during parasite cell death and is catalytically inactive at a pH of 8.0 or above. The presence, in the primary sequence, of an acidic amino acid-rich insertion exclusive to trypanosomatids and its spatial position in a homology-built model of LiEndoG led us to postulate that this peptide stretch might act as a pH sensor for self-inhibition. We found that a LiEndoG variant lacking residues 145-180 is indeed far more active than its wild-type counterpart at pH values >7...
September 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28877997/the-pumilio-domain-protein-puf6-contributes-to-sider2-retroposon-mediated-mrna-decay-in-leishmania
#8
Hiva Azizi, Carole Dumas, Barbara Papadopoulou
Leishmania and other trypanosomatid protozoa lack control at the level of transcription initiation and regulate gene expression exclusively posttranscriptionally. We have reported previously that Leishmania harbors a unique class of Short Interspersed DEgenerate Retroposons (SIDERs) that are predominantly located within 3'UTRs and play a major role in posttranscriptional control. We have shown that members of the SIDER2 subfamily initiate mRNA decay through endonucleolytic cleavage within the second conserved 79-nt signature sequence of SIDER2 retroposons...
September 6, 2017: RNA
https://www.readbyqxmd.com/read/28865321/in-silico-identification-of-inhibitors-of-ribose-5-phosphate-isomerase-from-trypanosoma-cruzi-using-ligand-and-structure-based-approaches
#9
Vanessa de V C Sinatti, Luiz Phillippe R Baptista, Marcelo Alves-Ferreira, Laurent Dardenne, João Hermínio Martins da Silva, Ana Carolina Guimarães
Chagas disease, caused by the protozoan Trypanosoma cruzi, affects approximately seven million people, mainly in Latin America, and causes about 7000 deaths annually. The available treatments are unsatisfactory and search for more effective drugs against this pathogen is critical. In this context, the ribose 5-phosphate isomerase (Rpi) enzyme is a potential drug target mainly due to its function in the pentose phosphate pathway and its essentiality (previously shown in other trypanosomatids). In this study, we propose novel potential inhibitors for the Rpi of T...
August 12, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28860337/from-b-to-a-making-an-essential-cofactor-in-a-human-parasite
#10
Naomi S Morrissette, Celia W Goulding
Trypanosomatids are parasitic eukaryotic organisms that cause human disease. These organisms have complex lifestyles; cycling between vertebrate and insect hosts and alternating between two morphologies; a replicating form and an infective, nonreplicating one. Because trypanosomatids are one of the few organisms that do not synthesize the essential cofactor, heme, these parasites sequester the most common form, heme B, from their hosts. Once acquired, the parasites derivatize heme B to heme A by two sequential enzyme reactions...
August 30, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28851417/development-of-conventional-and-real-time-multiplex-pcr-based-assays-for-estimation-of-natural-infection-rates-and-trypanosoma-cruzi-load-in-triatomine-vectors
#11
Otacilio C Moreira, Thaiane Verly, Paula Finamore-Araujo, Suzete A O Gomes, Catarina M Lopes, Danielle M de Sousa, Lívia R Azevedo, Fabio F da Mota, Claudia M d'Avila-Levy, Jacenir R Santos-Mallet, Constança Britto
BACKGROUND: Chagas disease is a complex anthropozoonosis with distinct domestic and sylvatic mammal species acting as potential reservoirs. The diversity of vector species and their habitats are among the factors that hinder the control of the disease. Control programs periodically monitor the prevalence of T. cruzi infection in insect bugs through microscopical observation of diluted feces. However, microscopy presents limited sensitivity in samples with low parasite numbers, difficulties in examining all evolutionary stages of the insect and may in turn be limited to differentiate T...
August 29, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28844718/nuclear-dna-replication-in-trypanosomatids-there-are-no-easy-methods-for-solving-difficult-problems
#12
REVIEW
Marcelo S da Silva, Raphael S Pavani, Jeziel D Damasceno, Catarina A Marques, Richard McCulloch, Luiz Ricardo Orsini Tosi, Maria Carolina Elias
In trypanosomatids, etiological agents of devastating diseases, replication is robust and finely controlled to maintain genome stability and function in stressful environments. However, these parasites encode several replication protein components and complexes that show potentially variant composition compared with model eukaryotes. This review focuses on the advances made in recent years regarding the differences and peculiarities of the replication machinery in trypanosomatids, including how such divergence might affect DNA replication dynamics and the replication stress response...
August 24, 2017: Trends in Parasitology
https://www.readbyqxmd.com/read/28841460/automatic-counting-of-trypanosomatid-amastigotes-in-infected-human-cells
#13
REVIEW
Cleber de Souza Relli, Jacques Facon, Horacio Legal Ayala, Alceu De Souza Britto
This article presents an automatic approach to counting amastigotes in human cells infected with Chagas. The approach is divided into four steps: first, morphological pretreatment removes the complex image background; sets are then segmented by unsupervised classification; the infected cells are then preserved using a thresholding process; and, finally, they undergo morphological granulometric processing and are filtered by the average. An experimental protocol was employed to compare the amastigotes nuclei labeled by a professional biochemist with the results obtained by the proposed approach...
August 10, 2017: Computers in Biology and Medicine
https://www.readbyqxmd.com/read/28827831/a-trypanosomal-orthologue-of-an-intermembrane-space-chaperone-has-a-non-canonical-function-in-biogenesis-of-the-single-mitochondrial-inner-membrane-protein-translocase
#14
Christoph Wenger, Silke Oeljeklaus, Bettina Warscheid, André Schneider, Anke Harsman
Mitochondrial protein import is essential for Trypanosoma brucei across its life cycle and mediated by membrane-embedded heterooligomeric protein complexes, which mainly consist of trypanosomatid-specific subunits. However, trypanosomes contain orthologues of small Tim chaperones that escort hydrophobic proteins across the intermembrane space. Here we have experimentally analyzed three novel trypanosomal small Tim proteins, one of which contains only an incomplete Cx3C motif. RNAi-mediated ablation of TbERV1 shows that their import, as in other organisms, depends on the MIA pathway...
August 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28822909/variation-in-basal-body-localisation-and-targeting-of-trypanosome-rp2-and-for20-proteins
#15
Jane Harmer, Xin Qi, Gabriella Toniolo, Aysha Patel, Hannah Shaw, Fiona E Benson, Michael L Ginger, Paul G McKean
TOF-LisH-PLL motifs define FOP family proteins; some members are involved in flagellum assembly. The critical role of FOP family protein FOR20 is poorly understood. Here, we report relative localisations of the four FOP family proteins in parasitic Trypanosoma brucei: TbRP2, TbOFD1 and TbFOP/FOP1-like are mature basal body proteins whereas TbFOR20 is present on pro- and mature basal bodies - on the latter it localises distal to TbRP2. We discuss how the data, together with published work for another protist Giardia intestinalis, informs on likely FOR20 function...
July 13, 2017: Protist
https://www.readbyqxmd.com/read/28780409/antiparasitic-activity-against-trypanosomatid-diseases-and-novel-metal-complexes-derived-from-the-first-time-characterized-5-phenyl-1-2-4-triazolo-1-5-a-pyrimidi-7-4h-one
#16
J M Méndez-Arriaga, G M Esteban-Parra, M J Juárez, A Rodríguez-Diéguez, M Sánchez-Moreno, J Isac-García, J M Salas
A serie of isostructural complexes with general formula [M(ftpO)2(H2O)4] have been obtained from reaction between the first time characterized triazolopyrimidine derivative 5-phenyl-1,2,4-triazolo[1,5-a]pyrimidi-7(4H)-one (HftpO) (1) and first row transition nitrates (M=Cu (2), Co (3), Ni (4) and Zn (5)). A copper complex with formula [Cu(HftpO)2(NO3)2(H2O)2]·H2O (6) was also isolated. HftpO and their metal complexes have been characterized by spectroscopic and thermal analysis and their crystal structures have been solved by X-ray diffraction methods...
July 29, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28767983/evidence-for-regulated-expression-of-telomeric-repeat-containing-rnas-terra-in-parasitic-trypanosomatids
#17
Jeziel D Damasceno, Gabriel LA Silva, Christian Tschudi, Luiz Ro Tosi
The Telomeric Repeat-containing RNAs (TERRA) participate in the homeostasis of telomeres in higher eukaryotes. Here, we investigated the expression of TERRA in Leishmania spp. and Trypanosoma brucei and found evidences for its expression as a specific RNA class. The trypanosomatid TERRA are heterogeneous in size and partially polyadenylated. The levels of TERRA transcripts appear to be modulated through the life cycle in both trypanosomatids investigated, suggesting that TERRA play a stage-specific role in the life cycle of these early-branching eukaryotes...
August 2017: Memórias do Instituto Oswaldo Cruz
https://www.readbyqxmd.com/read/28766182/lipidomics-and-anti-trypanosomatid-chemotherapy
#18
REVIEW
Michael Biagiotti, Sedelia Dominguez, Nader Yamout, Rachel Zufferey
BACKGROUND: Trypanosomatids such as Leishmania, Trypanosoma brucei and Trypanosoma cruzi belong to the order Kinetoplastida and are the source of many significant human and animal diseases. Current treatment is unsatisfactory and is compromised by the rising appearance of drug resistant parasites. Novel and more effective chemotherapeutics are urgently needed to treat and prevent these devastating diseases, which relies on the identification of essential, parasite specific targets that are absent in the host...
December 2017: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/28763686/in-silico-molecular-docking-studies-of-new-potential-4-phthalazinyl-hydrazones-on-selected-trypanosoma-cruzi-and-leishmania-enzyme-targets
#19
Angel H Romero, Simón E López
Recently, a series of 4-phthalazinyl-hydrazones under its E-configuration have exhibited excellent in vitro antichagasic and antileishmanial profiles. Preliminary assays on both parasites suggested that the most active derivatives act through oxidative and nitrosative stress mechanisms; however, their exact mode of actions as anti-trypanosomal and anti-leishmanial agents have not been completely elucidated. This motivated to perform a molecular docking study on essential trypanosomatid enzymes such as superoxide dismutase (SOD), trypanothione reductase (TryR), cysteine-protease (CP) and pteridine reductase 1 (PTR1)...
July 19, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28760415/surface-glycans-a-therapeutic-opportunity-for-kinetoplastid-diseases
#20
REVIEW
Víctor M Castillo-Acosta, Jan Balzarini, Dolores González-Pacanowska
Trypanosomal diseases are in need of innovative therapies that exploit novel mechanisms of action. The cell surface of trypanosomatid parasites is characterized by a dense coat of glycoconjugates with important functions in host cell recognition, immune evasion, infectivity, and cell function. The nature of parasite surface glycans is highly dynamic and changes during differentiation and in response to different stimuli through the action of glycosyltransferases and glycosidases. Here we propose a new approach to antiparasitic drug discovery that involves the use of carbohydrate-binding agents that bind specifically to cell-surface glycans, giving rise to cytotoxic events and parasite death...
July 28, 2017: Trends in Parasitology
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