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Trypanosomiasis

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https://www.readbyqxmd.com/read/28807574/synthesis-and-evaluation-of-analogs-of-5-z-4-amino-2-butenyl-methylamino-5-deoxyadenosine-mdl-73811-or-abeado-an-inhibitor-of-s-adenosylmethionine-decarboxylase-with-antitrypanosomal-activity
#1
Anthony J Brockway, Oleg A Volkov, Casey C Cosner, Karen S MacMillan, Stephen A Wring, Thomas E Richardson, Michael Peel, Margaret A Phillips, Jef K De Brabander
We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood-brain barrier permeation...
August 3, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28807005/first-records-of-triatoma-rubrofasciata-de-geer-1773-hemiptera-reduviidae-in-foshan-guangdong-province-southern-china
#2
Qin Liu, Yun-Hai Guo, Yi Zhang, Zheng-Bin Zhou, Liang-Liang Zhang, Dan Zhu, Xiao-Nong Zhou
BACKGROUND: Triatomines, also known as kissing bugs, which are found throughout the world and especially in Latin America, are well known natural vectors that transmit American trypanosomiasis, also called Chagas disease. In China, the presence of two species of Triatoma (Triatoma rubrofasciata and T. sinica) was recorded in the past. Due to the growing population and the increasing risk of the global spread of Chagas disease, triatomines became a potential public health nuisance, and in 2016, we started monitoring triatomine activities in southern China...
August 15, 2017: Infectious Diseases of Poverty
https://www.readbyqxmd.com/read/28804485/transcriptional-profiling-of-midguts-prepared-from-trypanosoma-t-congolense-positive-glossina-palpalis-palpalis-collected-from-two-distinct-cameroonian-foci-coordinated-signatures-of-the-midguts-remodeling-as-t-congolense-supportive-niches
#3
Jean M Tsagmo Ngoune, Flobert Njiokou, Béatrice Loriod, Ginette Kame-Ngasse, Nicolas Fernandez-Nunez, Claire Rioualen, Jacques van Helden, Anne Geiger
Our previous transcriptomic analysis of Glossina palpalis gambiensis experimentally infected or not with Trypanosoma brucei gambiense aimed to detect differentially expressed genes (DEGs) associated with infection. Specifically, we selected candidate genes governing tsetse fly vector competence that could be used in the context of an anti-vector strategy, to control human and/or animal trypanosomiasis. The present study aimed to verify whether gene expression in field tsetse flies (G. p. palpalis) is modified in response to natural infection by trypanosomes (T...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28792090/distinct-activation-mechanisms-trigger-the-trypanocidal-activity-of-dna-damaging-prodrugs
#4
Emma Louise Meredith, Ambika Kumar, Aya Konno, Joanna Szular, Sam Alsford, Karin Seifert, David Horn, Shane R Wilkinson
Quinone-based compounds have been exploited to treat infectious diseases and cancer, with such chemicals often functioning as inhibitors of key metabolic pathways or as prodrugs. Here, we screened an aziridinyl-1,4-benzoquinone (ABQ) library against the causative agents of trypanosomiasis, and cutaneous leishmaniasis, identifying several potent structures that exhibited EC50 values of <100 nM. However, these compounds also displayed significant toxicity towards mammalian cells indicating that they are not suitable therapies for systemic infections...
August 9, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28769924/thymic-stromal-lymphopoietin-is-critical-for-regulation-of-proinflammatory-cytokine-response-and-resistance-to-experimental-trypanosoma-congolense-infection
#5
Chukwunonso Onyilagha, Rani Singh, Abdelilah Soussi Gounni, Jude Ezeh Uzonna
African trypanosomiasis (sleeping sickness) poses serious threat to human and animal health in sub-Saharan Africa. Because there is currently no vaccine for preventing this disease and available drugs are not safe, understanding the mechanisms that regulate resistance and/or susceptibility to the disease could reveal novel targets for effective disease therapy and prevention. Thymic stromal lymphopoietin (TSLP) plays a critical role in driving Th2 immune response. Although susceptibility to experimental Trypanosoma congolense infection in mice is associated with excessive proinflammatory responses due in part to impaired Th2 response, the role of TSLP in resistance to African trypanosomiasis has not been well studied...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28752916/discovery-and-genomic-analyses-of-hybridization-between-divergent-lineages-of-trypanosoma-congolense-causative-agent-of-animal-african-trypanosomiasis
#6
Eliane Tihon, Hideo Imamura, Jean-Claude Dujardin, Jan Van Den Abbeele, Frederik Van den Broeck
Hybrid populations and introgressive hybridization remain poorly documented in pathogenic microorganisms, as such that genetic exchange has been argued to play a minor role in their evolution. Recent work demonstrated the existence of hybrid microsatellite profiles in Trypanosoma congolense, a parasitic protozoan with detrimental effects on livestock productivity in sub-Saharan Africa. Here we present the first population genomic study of T. congolense, revealing a remarkable number of Single Nucleotide Polymorphisms (SNPs), small insertions/deletions (indels) and gene deletions among 56 parasite genomes from ten African countries...
July 28, 2017: Molecular Ecology
https://www.readbyqxmd.com/read/28751930/the-correlation-between-chemical-structures-and-antioxidant-prooxidant-and-antitrypanosomatid-properties-of-flavonoids
#7
João Luiz Baldim, Bianca Gonçalves Vasconcelos de Alcântara, Olívia da Silva Domingos, Marisi Gomes Soares, Ivo Santana Caldas, Rômulo Dias Novaes, Tiago Branquinho Oliveira, João Henrique Ghilardi Lago, Daniela Aparecida Chagas-Paula
Flavonoids have demonstrated in vivo and in vitro leishmanicidal, trypanocidal, antioxidant, and prooxidant properties. The chemotherapy of trypanosomiasis and leishmaniasis lacks efficacy, presents high toxicity, and is related to the development of drug resistance. Thus, a series of 40 flavonoids were investigated with the purpose of correlating these properties via structure and activity analyses based on integrated networks and QSAR models. The classical groups for the antioxidant activity of flavonoids were combined in order to explain the influence of antioxidant and prooxidant activities on the antiparasitic properties...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28750007/adding-tsetse-control-to-medical-activities-contributes-to-decreasing-transmission-of-sleeping-sickness-in-the-mandoul-focus-chad
#8
Mahamat Hissene Mahamat, Mallaye Peka, Jean-Baptiste Rayaisse, Kat S Rock, Mahamat Abdelrahim Toko, Justin Darnas, Guihini Mollo Brahim, Ali Bachar Alkatib, Wilfrid Yoni, Inaki Tirados, Fabrice Courtin, Samuel P C Brand, Cyrus Nersy, Idriss Oumar Alfaroukh, Steve J Torr, Mike J Lehane, Philippe Solano
BACKGROUND: Gambian sleeping sickness or HAT (human African trypanosomiasis) is a neglected tropical disease caused by Trypanosoma brucei gambiense transmitted by riverine species of tsetse. A global programme aims to eliminate the disease as a public health problem by 2020 and stop transmission by 2030. In the South of Chad, the Mandoul area is a persistent focus of Gambian sleeping sickness where around 100 HAT cases were still diagnosed and treated annually until 2013. Pre-2014, control of HAT relied solely on case detection and treatment, which lead to a gradual decrease in the number of cases of HAT due to annual screening of the population...
July 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28750004/vertical-transmission-of-human-african-trypanosomiasis-clinical-evolution-and-brain-mri-of-a-mother-and-her-son
#9
Kathleen Gaillot, Marie-Agnès Lauvin, Jean-Philippe Cottier
No abstract text is available yet for this article.
July 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28740614/new-class-of-antitrypanosomal-agents-based-on-imidazopyridines
#10
Daniel G Silva, J Robert Gillespie, Ranae M Ranade, Zackary M Herbst, Uyen T T Nguyen, Frederick S Buckner, Carlos A Montanari, Michael H Gelb
The present work describes the synthesis of 22 new imidazopyridine analogues arising from medicinal chemistry optimization at different sites on the molecule. Seven and 12 compounds exhibited an in vitro EC50 ≤ 1 μM against Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) parasites, respectively. Based on promising results of in vitro activity (EC50 < 100 nM), cytotoxicity, metabolic stability, protein binding, and pharmacokinetics (PK) properties, compound 20 was selected as a candidate for in vivo efficacy studies...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28739368/andrographolide-induces-oxidative-stress-dependent-cell-death-in-unicellular-protozoan-parasite-trypanosoma-brucei
#11
Malabika Banerjee, Debaprasad Parai, Pranab Dhar, Manab Roy, Rajib Barik, Subrata Chattopadhyay, Samir Kumar Mukherjee
African sleeping sickness is a parasitic disease in humans and livestock caused by Trypanosoma brucei throughout sub-Saharan Africa. Absence of appropriate vaccines and prevalence of drug resistance proclaim that a new way of therapeutic interventions is essential against African trypanosomiasis. In the present study, we have looked into the effect of andrographolide (andro), a diterpenoid lactone from Andrographis paiculata on Trypanosoma brucei PRA 380. Although andro has been recognized as a promosing anti-cancer drug, its usefulness against Trypanosoma spp remained unexplored...
July 21, 2017: Acta Tropica
https://www.readbyqxmd.com/read/28733613/rnai-screening-identifies-trypanosoma-brucei-stress-response-protein-kinases-required-for-survival-in-the-mouse
#12
Fernando Fernandez-Cortes, Tiago D Serafim, Jonathan M Wilkes, Nathaniel G Jones, Ryan Ritchie, Richard McCulloch, Jeremy C Mottram
Protein kinases (PKs) are a class of druggable targets in Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (sleeping sickness), yet little is known about which PKs are essential for survival in mammals. A recent kinome-wide RNAi screen with 176 individual bloodstream form Trypanosoma brucei lines identified PKs required for proliferation in culture. In order to assess which PKs are also potential virulence factors essential in vivo, lines were pooled, inoculated into mice, and screened for loss of fitness after 48 h RNAi...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28723901/2b-rad-genotyping-for-population-genomic-studies-of-chagas-disease-vectors-rhodnius-ecuadoriensis-in-ecuador
#13
Luis E Hernandez-Castro, Marta Paterno, Anita G Villacís, Björn Andersson, Jaime A Costales, Michele De Noia, Sofía Ocaña-Mayorga, Cesar A Yumiseva, Mario J Grijalva, Martin S Llewellyn
BACKGROUND: Rhodnius ecuadoriensis is the main triatomine vector of Chagas disease, American trypanosomiasis, in Southern Ecuador and Northern Peru. Genomic approaches and next generation sequencing technologies have become powerful tools for investigating population diversity and structure which is a key consideration for vector control. Here we assess the effectiveness of three different 2b restriction site-associated DNA (2b-RAD) genotyping strategies in R. ecuadoriensis to provide sufficient genomic resolution to tease apart microevolutionary processes and undertake some pilot population genomic analyses...
July 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28713367/nanobodies-as-tools-to-understand-diagnose-and-treat-african-trypanosomiasis
#14
REVIEW
Benoit Stijlemans, Patrick De Baetselier, Guy Caljon, Jan Van Den Abbeele, Jo A Van Ginderachter, Stefan Magez
African trypanosomes are strictly extracellular protozoan parasites that cause diseases in humans and livestock and significantly affect the economic development of sub-Saharan Africa. Due to an elaborate and efficient (vector)-parasite-host interplay, required to complete their life cycle/transmission, trypanosomes have evolved efficient immune escape mechanisms that manipulate the entire host immune response. So far, not a single field applicable vaccine exists, and chemotherapy is the only strategy available to treat the disease...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28706938/inhibitors-of-glycosomal-protein-import-provide-new-leads-against-trypanosomiasis
#15
COMMENT
Vishal C Kalel, Leonidas Emmanouilidis, Maciej Dawidowski, Wolfgang Schliebs, Michael Sattler, Grzegorz M Popowicz, Ralf Erdmann
Vector-borne trypanosomatid parasite infections in tropical and sub-tropical countries constitute a major threat to humans and livestock. Trypanosoma brucei parasites are transmitted by tsetse fly and lead to African sleeping sickness in humans and Nagana in cattle. In Latin American countries, Trypanosoma cruzi infections spread by triatomine kissing bugs lead to Chagas disease. Various species of Leishmania transmitted to humans by phlebotomine sandflies manifest in a spectrum of diseases termed Leishmaniasis...
July 3, 2017: Microbial Cell
https://www.readbyqxmd.com/read/28698054/bistacrines-as-potential-antitrypanosomal-agents
#16
Ines Schmidt, Sarah Göllner, Antje Fuß, August Stich, Anna Kucharski, Tanja Schirmeister, Elena Katzowitsch, Heike Bruhn, Alexandra Miliu, R Luise Krauth-Siegel, Ulrike Holzgrabe
Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity...
August 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28697609/differential-virulence-and-tsetse-fly-transmissibility-of-i-trypanosoma-congolense-i-and-i-trypanosoma-brucei-i-strains
#17
Purity K Gitonga, Kariuki Ndung'u, Grace A Murilla, Paul C Thande, Florence N Wamwiri, Joanna E Auma, Geoffrey N Ngae, James K Kibugu, Richard Kurgat, John K Thuita
African animal trypanosomiasis causes significant economic losses in sub-Saharan African countries because of livestock mortalities and reduced productivity. Trypanosomes, the causative agents, are transmitted by tsetse flies (Glossina spp.). In the current study, we compared and contrasted the virulence characteristics of five Trypanosoma congolense and Trypanosoma brucei isolates using groups of Swiss white mice (n = 6). We further determined the vectorial capacity of Glossina pallidipes, for each of the trypanosome isolates...
June 27, 2017: Onderstepoort Journal of Veterinary Research
https://www.readbyqxmd.com/read/28684718/steroid-alkaloids-from-holarrhena-africana-with-strong-activity-against-trypanosoma-brucei-rhodesiense
#18
Charles Okeke Nnadi, Ngozi Justina Nwodo, Marcel Kaiser, Reto Brun, Thomas J Schmidt
In our continued search for natural compounds with activity against Trypanosoma brucei, causative agent of human African trypanosomiasis (HAT, "sleeping sickness"), we have investigated extracts from the leaves and bark of the West African Holarrhenaafricana (syn. Holarrhena floribunda; Apocynaceae). The extracts and their alkaloid-enriched fractions displayed promising in vitro activity against bloodstream forms of T. brucei rhodesiense (Tbr; East African HAT). Bioactivity-guided chromatographic fractionation of the alkaloid-rich fractions resulted in the isolation of 17 steroid alkaloids, one nitrogen-free steroid and one alkaloid-like non-steroid...
July 6, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28684709/trypanosoma-brucei-inhibition-by-essential-oils-from-medicinal-and-aromatic-plants-traditionally-used-in-cameroon-azadirachta-indica-aframomum-melegueta-aframomum-daniellii-clausena-anisata-dichrostachys-cinerea-and-echinops-giganteus
#19
Stephane L Ngahang Kamte, Farahnaz Ranjbarian, Gustavo Daniel Campagnaro, Prosper C Biapa Nya, Hélène Mbuntcha, Verlaine Woguem, Hilaire Macaire Womeni, Léon Azefack Ta, Cristiano Giordani, Luciano Barboni, Giovanni Benelli, Loredana Cappellacci, Anders Hofer, Riccardo Petrelli, Filippo Maggi
Essential oils are complex mixtures of volatile components produced by the plant secondary metabolism and consist mainly of monoterpenes and sesquiterpenes and, to a minor extent, of aromatic and aliphatic compounds. They are exploited in several fields such as perfumery, food, pharmaceutics, and cosmetics. Essential oils have long-standing uses in the treatment of infectious diseases and parasitosis in humans and animals. In this regard, their therapeutic potential against human African trypanosomiasis (HAT) has not been fully explored...
July 6, 2017: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/28679527/ornithine-uptake-and-the-modulation-of-drug-sensitivity-in-trypanosoma-brucei
#20
Juan P Macedo, Rachel B Currier, Corina Wirdnam, David Horn, Sam Alsford, Doris Rentsch
Trypanosoma brucei, protozoan parasites that cause human African trypanosomiasis (HAT), depend on ornithine uptake and metabolism by ornithine decarboxylase (ODC) for survival. Indeed, ODC is the target of the WHO "essential medicine" eflornithine, which is antagonistic to another anti-HAT drug, suramin. Thus, ornithine uptake has important consequences in T. brucei, but the transporters have not been identified. We describe these amino acid transporters (AATs). In a heterologous expression system, TbAAT10-1 is selective for ornithine, whereas TbAAT2-4 transports both ornithine and histidine...
July 5, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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