keyword
https://read.qxmd.com/read/38484800/resolving-the-polycistronic-aftermath-essential-role-of-topoisomerase-ia-in-preventing-r-loops-in-leishmania
#1
JOURNAL ARTICLE
Payel Das, Arnab Hazra, Saradindu Saha, Sadhana Roy, Mandrita Mukherjee, Saugata Hazra, H K Majumdar, Somdeb BoseDasgupta
Kinetoplastid parasites are 'living bridges' in the evolution from prokaryotes to higher eukaryotes. The near-intronless genome of the kinetoplastid Leishmania, exhibit polycistronic transcription which can facilitate R-loop formation. Therefore, to prevent such DNA-RNA hybrids Leishmania has retained prokaryotic-like DNA Topoisomerase IA (LdTOPIA) in course of evolution. LdTOPIA is an essential enzyme which is expressed ubiquitously and is adapted for the compartmentalized eukaryotic form in harboring functional bipartite nuclear localization signals...
March 12, 2024: Journal of Biological Chemistry
https://read.qxmd.com/read/38484645/acrylonitrile-derivatives-in-vitro-activity-and-mechanism-of-cell-death-induction-against-trypanosoma-cruzi-and-leishmania-amazonensis
#2
JOURNAL ARTICLE
Carlos J Bethencourt-Estrella, Samuel Delgado-Hernández, Atteneri López-Arencibia, Desirée San Nicolás-Hernández, Lizbeth Salazar-Villatoro, Maritza Omaña-Molina, David Tejedor, Fernando García-Tellado, Jacob Lorenzo-Morales, José E Piñero
Leishmaniasis and Chagas disease are parasitic infections that affect millions of people worldwide, producing thousands of deaths per year. The current treatments against these pathologies are not totally effective and produce some side effects in the patients. Acrylonitrile derivatives are a group of compounds that have shown activity against these two diseases. In this work, four novels synthetic acrylonitriles were evaluated against the intracellular form and extracellular forms of L. amazonensis and T. cruzi...
March 6, 2024: International Journal for Parasitology, Drugs and Drug Resistance
https://read.qxmd.com/read/38481660/vaccination-with-parasite-specific-tctasv-proteins-combined-with-recombinant-baculovirus-as-a-delivery-platform-protects-against-acute-and-chronic-trypanosoma-cruzi-infection
#3
JOURNAL ARTICLE
Yamil E Masip, Lucas D Caeiro, Maximiliano Cosenza, Miriam Postan, Guido Molina, Oscar Taboga, María Paula Molinari, Valeria Tekiel
Chagas' is a neglected disease caused by the eukaryotic kinetoplastid parasite, Trypanosoma cruzi. Currently, approximately 8 million people are infected worldwide, most of whom are in the chronic phase of the disease, which involves cardiac, digestive, or neurologic manifestations. There is an urgent need for a vaccine because treatments are only effective in the initial phase of infection, which is generally underdiagnosed. The selection and combination of antigens, adjuvants, and delivery platforms for vaccine formulations should be designed to trigger mixed humoral and cellular immune responses, considering that T...
2024: Frontiers in Cellular and Infection Microbiology
https://read.qxmd.com/read/38453826/nmr-study-of-the-structure-and-dynamics-of-the-brct-domain-from-the-kinetochore-protein-kkt4
#4
JOURNAL ARTICLE
Patryk Ludzia, Hanako Hayashi, Timothy Robinson, Bungo Akiyoshi, Christina Redfield
KKT4 is a multi-domain kinetochore protein specific to kinetoplastids, such as Trypanosoma brucei. It lacks significant sequence similarity to known kinetochore proteins in other eukaryotes. Our recent X-ray structure of the C-terminal region of KKT4 shows that it has a tandem BRCT (BRCA1 C Terminus) domain fold with a sulfate ion bound in a typical binding site for a phosphorylated serine or threonine. Here we present the 1 H, 13 C and 15 N resonance assignments for the BRCT domain of KKT4 (KKT4463-645 ) from T...
March 7, 2024: Biomolecular NMR Assignments
https://read.qxmd.com/read/38447055/distribution-and-functional-analysis-of-isocitrate-dehydrogenases-across-kinetoplastids
#5
JOURNAL ARTICLE
Ľubomíra Chmelová, Kristína Záhonová, Amanda T S Albanaz, Liudmyla Hrebenyk, Anton Horváth, Vyacheslav Yurchenko, Ingrid Škodová-Sveráková
Isocitrate dehydrogenase (IDH) is an enzyme converting isocitrate to α-ketoglutarate in the canonical tricarboxylic acid (TCA) cycle. There are three different types of IDH documented in eukaryotes. Our study points out the complex evolutionary history of IDHs across kinetoplastids, where the common ancestor of Trypanosomatidae and Bodonidae was equipped with two isoforms of the IDH enzyme: the NADP+-dependent IDH1 with possibly dual localization in the cytosol and mitochondrion and NADP+-dependent mitochondrial IDH2...
March 6, 2024: Genome Biology and Evolution
https://read.qxmd.com/read/38442428/monitoring-the-long-term-effectiveness-of-miltefosine-in-indian-post-kala-azar-dermal-leishmaniasis
#6
JOURNAL ARTICLE
Sutopa Roy, Srija Moulik, Madhurima Roy, Manab K Ghosh, Surya Jyati Chaudhuri, Dhruv K Pandey, Saurabh Jain, Daniel Argaw Dagne, Mitali Chatterjee
Post-kala-azar dermal leishmaniasis (PKDL), the dermal sequel to visceral leishmaniasis (VL), is characterized by hypopigmented macules (macular) and/or papules and nodules (polymorphic). Post-kala-azar dermal leishmaniasis plays a significant role in disease transmission, emphasizing the need for monitoring chemotherapeutic effectiveness. Accordingly, this study aimed to quantify the parasite burden in PKDL patients after treatment with miltefosine by a quantitative polymerase chain reaction (qPCR). A Leishmania kinetoplastid gene-targeted qPCR was undertaken using DNA from skin biopsy specimens of patients with PKDL at three time points, i...
March 5, 2024: American Journal of Tropical Medicine and Hygiene
https://read.qxmd.com/read/38401850/mapping-the-transporter-substrate-interactions-of-the-trypanosoma-cruzi-nb1-nucleobase-transporter-reveals-the-basis-for-its-high-affinity-and-selectivity-for-hypoxanthine-and-guanine-and-lack-of-nucleoside-uptake
#7
JOURNAL ARTICLE
Mustafa M Aldfer, Fabian Hulpia, Serge van Calenbergh, Harry P De Koning
Trypanosoma cruzi is a protozoan parasite and the etiological agent of Chagas disease, a debilitating and sometimes fatal disease that continues to spread to new areas. Yet, Chagas disease is still only treated with two related nitro compounds that are insufficiently effective and cause severe side effects. Nucleotide metabolism is one of the known vulnerabilities of T. cruzi, as they are auxotrophic for purines, and nucleoside analogues have been shown to have genuine promise against this parasite in vitro and in vivo...
February 22, 2024: Molecular and Biochemical Parasitology
https://read.qxmd.com/read/38363808/linear-motifs-regulating-protein-secretion-sorting-and-autophagy-in-leishmania-parasites-are-diverged-with-respect-to-their-host-equivalents
#8
JOURNAL ARTICLE
Andras Zeke, Toby J Gibson, Laszlo Dobson
The pathogenic, tropical Leishmania flagellates belong to an early-branching eukaryotic lineage (Kinetoplastida) with several unique features. Unfortunately, they are poorly understood from a molecular biology perspective, making development of mechanistically novel and selective drugs difficult. Here, we explore three functionally critical targeting short linear motif systems as well as their receptors in depth, using a combination of structural modeling, evolutionary sequence divergence and deep learning...
February 16, 2024: PLoS Computational Biology
https://read.qxmd.com/read/38323082/polymeric-nanoparticles-containing-kojic-acid-induce-structural-alterations-and-apoptosis-like-death-in-leishmania-leishmania-amazonensis
#9
JOURNAL ARTICLE
Poliana Queiroz-Souza, Adan Galue-Parra, Lienne Silveira Moraes, Caroline Gomes Macedo, Ana Paula Drummond Rodrigues, Victor H S Marinho, Fabricio H Holanda, Irlon M Ferreira, Edilene Oliveira da Silva
Leishmaniasis encompasses a cluster of neglected tropical diseases triggered by kinetoplastid phatogens belonging to the genus Leishmania. Current therapeutic approaches are toxic, expensive, and require long-term treatment. Nanoparticles are emerging as a new alternative for the treatment of neglected tropical diseases. Silk Fibroin is a biocompatible and amphiphilic protein that can be used for formulating nanoemulsions, while kojic acid is a secondary metabolite with antileishmanial actions. Thus, this study evaluated the efficacy of a nanoemulsion, formulated with silk fibroin as the surfactant and containing kojic acid (NanoFKA), against promastigote and amastigote forms of Leishmania ( Leishmania ) amazonensis ...
2024: Frontiers in Pharmacology
https://read.qxmd.com/read/38299836/the-intersection-of-host-in-vivo-metabolism-and-immune-responses-to-infection-with-kinetoplastid-and-apicomplexan-parasites
#10
REVIEW
Sarah Ewald, Azadeh Nasuhidehnavi, Tzu-Yu Feng, Mahbobeh Lesani, Laura-Isobel McCall
SUMMARYProtozoan parasite infection dramatically alters host metabolism, driven by immunological demand and parasite manipulation strategies. Immunometabolic checkpoints are often exploited by kinetoplastid and protozoan parasites to establish chronic infection, which can significantly impair host metabolic homeostasis. The recent growth of tools to analyze metabolism is expanding our understanding of these questions. Here, we review and contrast host metabolic alterations that occur in vivo during infection with Leishmania , trypanosomes, Toxoplasma , Plasmodium, and Cryptosporidium ...
February 1, 2024: Microbiology and Molecular Biology Reviews: MMBR
https://read.qxmd.com/read/38295092/comparative-genomics-of-leishmania-donovani-progeny-from-genetic-crosses-in-two-sand-fly-species-and-impact-on-the-diversity-of-diagnostic-and-vaccine-candidates
#11
JOURNAL ARTICLE
Jovana Sádlová, Matthew Yeo, David S Mateus, Jody Phelan, Le Anh Hai, Tapan Bhattacharyya, Stefan Kurtev, Ondrej Sebesta, Jitka Myskova, Veronika Seblova, Björn Andersson, Paola Florez de Sessions, Petr Volf, Michael A Miles
Sand fly transmitted Leishmania species are responsible for severe, wide ranging, visceral and cutaneous leishmaniases. Genetic exchange can occur among natural Leishmania populations and hybrids can now be produced experimentally, with limitations. Feeding Phlebotomus orientalis or Phlebotomus argentipes on two strains of Leishmania donovani yielded hybrid progeny, selected using double drug resistance and fluorescence markers. Fluorescence activated cell sorting of cultured clones derived from these hybrids indicated diploid progeny...
January 2024: PLoS Neglected Tropical Diseases
https://read.qxmd.com/read/38293145/an-unconventional-regulatory-circuitry-involving-aurora-b-controls-anaphase-onset-and-error-free-chromosome-segregation-in-trypanosomes
#12
Daniel Ballmer, Hua Jane Lou, Midori Ishii, Benjamin E Turk, Bungo Akiyoshi
Accurate chromosome segregation during mitosis requires that all chromosomes establish stable bi-oriented attachments with the spindle apparatus. Kinetochores form the interface between chromosomes and spindle microtubules and as such are under tight control by complex regulatory circuitry. As part of the chromosomal passenger complex (CPC), the Aurora B kinase plays a central role within this circuitry by destabilizing improper kinetochore-microtubule attachments and relaying the attachment status to the spindle assembly checkpoint, a feedback control system that delays the onset of anaphase by inhibiting the anaphase-promoting complex/cyclosome...
January 20, 2024: bioRxiv
https://read.qxmd.com/read/38254667/unwrap-rap1-s-mystery-at-kinetoplastid-telomeres
#13
REVIEW
Bibo Li
Although located at the chromosome end, telomeres are an essential chromosome component that helps maintain genome integrity and chromosome stability from protozoa to mammals. The role of telomere proteins in chromosome end protection is conserved, where they suppress various DNA damage response machineries and block nucleolytic degradation of the natural chromosome ends, although the detailed underlying mechanisms are not identical. In addition, the specialized telomere structure exerts a repressive epigenetic effect on expression of genes located at subtelomeres in a number of eukaryotic organisms...
January 4, 2024: Biomolecules
https://read.qxmd.com/read/38223920/molecular-monitoring-of-treatment-efficacy-in-human-visceral-leishmaniasis
#14
JOURNAL ARTICLE
Sutopa Roy, Srija Moulik, Surya Jyati Chaudhuri, Manab K Ghosh, R P Goswami, Bibhuti Saha, Mitali Chatterjee
BACKGROUND: Focused efforts of the visceral leishmaniasis elimination program have led to a drastic decline in cases, and the present challenge is disease monitoring, which this study aimed to assess. METHODS: A Leishmania kinetoplastid-targeted qPCR quantified parasite load at disease presentation, and following treatment completion (n=49); an additional 80 cases were monitored after completion of treatment. RESULTS: The parasite load at disease presentation was 13 461...
January 15, 2024: Transactions of the Royal Society of Tropical Medicine and Hygiene
https://read.qxmd.com/read/38187297/the-role-of-tryptophan-derivatives-as-anti-kinetoplastid-agents
#15
REVIEW
Ewura-Esi Manful, Aboagye Kwarteng Dofuor, Theresa Manful Gwira
Kinetoplastids are the causative agents for a spectrum of vector-borne diseases including Leishmaniasis, Chagas disease and Trypanosomiasis that affect millions of people worldwide. In the absence of safe and effective vaccines, chemotherapy, in conjunction with vector control, remain the most significant control approach for kinetoplastid diseases. However, commercially available treatment for these neglected tropical diseases frequently ends up with toxic side effects and increasing resistance. To meet the rising need for innovative medications, alternative chemotherapeutic agents are required...
January 15, 2024: Heliyon
https://read.qxmd.com/read/38141899/evaluation-of-the-accuracy-of-a-multi-infection-screening-test-based-on-a-multiplex-immunoassay-targeting-imported-diseases-common-in-migrant-populations
#16
JOURNAL ARTICLE
Ruth Aguilar, Angeline Cruz, Alfons Jiménez, Alex Almuedo, Carme Roca Saumell, Marina Gigante Lopez, Oriol Gasch, Gemma Falcó, Ana Jiménez-Lozano, Angela Martínez-Perez, Consol Sanchez-Collado, Andrea Tedesco, Manuel Carlos López, María Jesús Pinazo, Thais Leonel, Zeno Bisoffi, Anna Färnert, Carlota Dobaño, Ana Requena-Méndez
BACKGROUND: We aimed to evaluate the performance of a novel multiplex serological assay, able to simultaneously detect IgG of six infections, as a screening tool for imported diseases in migrants. METHODS: Six panels of 40 (n = 240) anonymized serum samples with confirmed infections were used as positive controls to assess the multiplex assay's sensitivity. One panel of 40 sera from non-infected subjects was used to estimate the seropositivity cutoffs, and 32 non-infected sera were used as negative controls to estimate each serology's sensitivity and specificity...
December 21, 2023: Travel Medicine and Infectious Disease
https://read.qxmd.com/read/38126788/genome-wide-screens-connect-hd82-loss-of-function-to-purine-analog-resistance-in-african-trypanosomes
#17
JOURNAL ARTICLE
Anna Trenaman, Michele Tinti, Abdelmadjid Atrih, David Horn
There is substantial interest in developing nucleoside analogs as anti-parasitic agents. We used genome-scale genetic screening and discovered two proteins linked to purine analog resistance in African trypanosomes. Our screens also identified two nucleoside kinases required for pro-drug activation, further validating the approach. The top novel hit, HD82, is related to SAMHD1, a mammalian nuclear viral restriction factor. We validated HD82 and localized the protein to the trypanosome nucleus. HD82 appears to sensitize trypanosomes to nucleoside analogs by reducing native pools of nucleotides, providing insights into both nucleoside/nucleotide metabolism and nucleoside analog resistance in trypanosomatids...
December 21, 2023: MSphere
https://read.qxmd.com/read/38032881/the-indole-motif-is-essential-for-the-antitrypanosomal-activity-of-n5-substituted-paullones
#18
JOURNAL ARTICLE
Irina Ihnatenko, Marco J Müller, Oliver C F Orban, Jens C Lindhof, Diego Benítez, Cecilia Ortíz, Estefanía Dibello, Leonardo L Seidl, Marcelo A Comini, Conrad Kunick
Severe infections with potentially fatal outcomes are caused by parasites from the genera Trypanosoma and Leishmania (class Kinetoplastea). The diseases affect people of remote areas in the tropics and subtropics with limited access to adequate health care. Besides insufficient diagnostics, treatment options are limited, with tenuous developments in recent years. Therefore, new antitrypanosomal antiinfectives are required to fight these maladies. In the presented approach, new compounds were developed and tested on the target trypanothione synthetase (TryS)...
2023: PloS One
https://read.qxmd.com/read/38010644/disruption-of-leishmania-flagellum-attachment-zone-architecture-causes-flagellum-loss
#19
JOURNAL ARTICLE
Clare Halliday, Laryssa Vanessa de Liz, Sue Vaughan, Jack D Sunter
Leishmania are flagellated eukaryotic parasites that cause leishmaniasis and are closely related to the other kinetoplastid parasites such as Trypanosoma brucei. In all these parasites there is a cell membrane invagination at the base of the flagellum called the flagellar pocket, which is tightly associated with and sculpted by cytoskeletal structures including the flagellum attachment zone (FAZ). The FAZ is a complex interconnected structure linking the flagellum to the cell body and has critical roles in cell morphogenesis, function and pathogenicity...
November 27, 2023: Molecular Microbiology
https://read.qxmd.com/read/37995979/high-throughput-screening-of-compounds-targeting-rna-editing-in-trypanosoma-brucei-novel-molecular-scaffolds-with-broad-trypanocidal-effects
#20
JOURNAL ARTICLE
Mojtaba Rostamighadi, Arezou Kamelshahroudi, Vaibhav Mehta, Fu-Yue Zeng, Ian Pass, Thomas D Y Chung, Reza Salavati
Mitochondrial uridine insertion/deletion RNA editing, catalyzed by a multiprotein complex (editosome), is essential for gene expression in trypanosomes and Leishmania parasites. As this process is absent in the human host, a drug targeting this mechanism promises high selectivity and reduced toxicity. Here, we successfully miniaturized our FRET-based full-round RNA editing assay, which replicates the complete RNA editing process, adapting it into a 1536-well format. Leveraging this assay, we screened over 100,000 compounds against purified editosomes derived from Trypanosoma brucei, identifying seven confirmed primary hits...
November 21, 2023: Biochemical Pharmacology
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