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Nidhi Singh, Priyanka Shah, Hemlata Dwivedi, Shikha Mishra, Renu Tripathi, Amogh A Sahasrabuddhe, Mohammad Imran Siddiqi
N-Myristoyltransferase (NMT) catalyzes the transfer of myristate to the amino-terminal glycine of a subset of proteins, a co-translational modification involved in trafficking substrate proteins to membrane locations, stabilization and protein-protein interactions. It is a studied and validated pre-clinical drug target for fungal and parasitic infections. In the present study, a machine learning approach, docking studies and CoMFA analysis have been integrated with the objective of translation of knowledge into a pipelined workflow towards the identification of putative hits through the screening of large compound libraries...
October 21, 2016: Molecular BioSystems
Matías Hernández, Susana Wicz, Ricardo S Corral
BACKGROUND: Diverse cardiovascular signaling routes have been considered critical for Chagas cardiomyopathy caused by the protozoan parasite Trypanosoma cruzi. Along this line, T. cruzi infection and endothelin-1 (ET-1) have been shown to cooperatively activate the Ca(2+)/NFAT cascade in cardiomyocytes, leading to cyclooxygenase type 2 (COX-2) induction and increased release of prostanoids and prohypertrophic peptides. PURPOSE: To determine whether the well-known cardioprotective and anti-inflammatory effects of curcumin (Cur) could be helpful to interfere with this key machinery for pathogenesis of Chagas myocarditis...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Xianxiu Wan, Jian-Jun Wen, Sue-Jie Koo, Lisa Yi Liang, Nisha Jain Garg
Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes and integrates mitochondrial metabolism and inflammation; and SIRT1 deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infected with Trypanosoma cruzi (Tc), treated with SIRT1 agonists (resveratrol or SRT1720), and monitored during chronic phase (~150 days post-infection). Resveratrol treatment was partially beneficial in controlling the pathologic processes in Chagas disease...
October 2016: PLoS Pathogens
Nurkhalida Kamal, Christina V Viegelmann, Carol J Clements, RuAngelie Edrada-Ebel
Fungal endophytes offer diverse and unique secondary metabolites, making these organisms potential sources of promising drug leads. The application of high-resolution-liquid chromatography mass spectrometry and nuclear magnetic resonance-based metabolomics to fungal endophytes is practical in terms of dereplication studies and the mining of bioactive compounds. In this paper, we report the application of metabolomics in parallel with anti-trypanosomal assays to determine the ideal conditions for the medium-scale fermentation of the endophyte Lasiodiplodia theobromae...
October 19, 2016: Planta Medica
Camila Oliveira, Paulo Costa Carvalho, Lysangela Ronalte Alves, Samuel Goldenberg
The regulation of gene expression in trypanosomatids occurs mainly at the post-transcriptional level. Despite the importance of this type of control in Trypanosoma cruzi, few RNA binding proteins have been characterized. The RRM domain (RNA Recognition Motif) is one of the most abundant domains found in RNA-binding proteins in higher eukaryotes. Proteins containing the RRM domain are involved in the majority of post-transcriptional processes regulating gene expression. In this work, we aimed to characterize the protein TcNRBD1 from T...
2016: PloS One
Alice Ricardo-Silva, Teresa Cristina Monte Gonçalves, José Francisco Luitgards-Moura, Catarina Macedo Lopes, Silvano Pedrosa da Silva, Amanda Queiroz Bastos, Nathalia Coelho Vargas, Maria-Rosa Goreti Freitas
During a medical entomology course in Boa Vista, Roraima, colonies of Triatoma maculata closely associated with pigeon nests were observed in concrete air-conditioner box located on the external plastered and cemented walls of a modern brick-built apartment block. In only one eight-hole ceramic brick, located inside one air-conditioner box, 127 specimens of T. maculata were collected. T. maculata is a recognised vector of Trypanosoma cruzi in the surrounding area and its domiciliation increases the risk of Chagas disease transmission...
October 13, 2016: Memórias do Instituto Oswaldo Cruz
Juan Felipe Osorio-Méndez, Andrea Vizcaíno-Castillo, Rebeca Manning-Cela, Roberto Hernandez, Ana María Cevallos
The role and regulation of actin in Trypanosoma cruzi and other related parasites is largely unknown. Based on early genome analysis, it was proposed that there was a reduced dependency on the acto-myosin system in the trypanosomatid parasites. However, more recent studies have extended the set of potential actin regulatory proteins, particularly for T. cruzi. One of the identified actin-binding proteins in trypanosomatids is profilin. In other systems, it is capable of simultaneously binding both monomeric actin and several actin-regulatory factors...
October 15, 2016: Biochemical and Biophysical Research Communications
Sebastian Hutchinson, Lucy Glover, David Horn
BACKGROUND: African trypanosomes cause lethal diseases in humans and animals and escape host immune attack by switching the expression of Variant Surface Glycoprotein (VSG) genes. The expressed VSGs are located at the ends of telomeric, polycistronic transcription units known as VSG expression sites (VSG-ESs). Each cell has many VSG-ESs but only one is transcribed in bloodstream-form parasites and all of them are inactive upon transmission to the insect vector mid-gut; a subset of monocistronic metacyclic VSG-ESs are then activated in the insect salivary gland...
October 18, 2016: BMC Genomics
J A DE Fuentes-Vicente, M Cabrera-Bravo, J N Enríquez-Vara, M I Bucio-Torres, A E Gutiérrez-Cabrera, D G Vidal-López, J A Martínez-Ibarra, P M Salazar-Schettino, A Córdoba-Aguilar
Little is known about how the virulence of a human pathogen varies in the environment it shares with its vector. This study focused on whether the virulence of Trypanosoma cruzi (Trypanosomatida: Trypanosomatidae), the causal agent of Chagas' disease, is related to altitude. Accordingly, Triatoma dimidiata (Hemiptera: Reduviidae) specimens were collected at three different altitudes (300, 700 and 1400 m a.s.l.) in Chiapas, Mexico. The parasite was then isolated to infect uninfected T. dimidiata from the same altitudes, as well as female CD-1 mice...
October 18, 2016: Medical and Veterinary Entomology
Zheng Liu, Cristina Gutierrez-Vargas, Jia Wei, Robert A Grassucci, Noel Espina, Susan Madison-Antenucci, Liang Tong, Joachim Frank
With the advance of new instruments and algorithms, and the accumulation of experience over decades, single-particle cryo-EM has become a pivotal part of structural biology. Recently, we determined the structure of a eukaryotic ribosome at 2.5 Å for the large subunit. The ribosome was derived from Trypanosoma cruzi, the protozoan pathogen of Chagas disease. The high-resolution density map allowed us to discern a large number of unprecedented details including rRNA modifications, water molecules, and ions such as Mg(2+) and Zn(2+) ...
October 17, 2016: Protein Science: a Publication of the Protein Society
Amanda Fortes Francisco, Shiromani Jayawardhana, Michael D Lewis, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Maria Osuna-Cabello, Kevin D Read, Susan A Charman, Eric Chatelain, John M Kelly
The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure...
October 17, 2016: Scientific Reports
Matheus D Baldissera, Carine F Souza, Thirssa H Grando, Geisa S Dolci, Luciana F Cossetin, Karen L S Moreira, Marcelo L DA Veiga, Maria Izabel U M DA Rocha, Aline A Boligon, Marli M A DE Campos, Lenita M Stefani, Aleksandro S DA Silva, Silvia G Monteiro
The aim of this study was to evaluate the effect of nerolidol free (N-F) and nerolidol-loaded in nanospheres (N-NS) on the hepatic antioxidant/oxidant status of mice experimentally infected by Trypanosoma evansi. In the liver it was measured: reactive oxygen species (ROS), thiobarbituric reactive acid substances (TBARS) and non-protein thiols (NPSH), catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST) and performed histopathological examination. In addition, seric levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured...
October 17, 2016: Parasitology
Jian-Jun Wen, Xianxiu Wan, John Thacker, Nisha Jain Garg
BACKGROUND: Chagasic cardiomyopathy (CCM) caused by Trypanosoma cruzi (Tc) infection is prevalent in Latin America and recognized as an emerging infectious heart disease in the US. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy and may be disturbed due to phosphodiesterase (PDE5) mediated cGMP catabolism in CCM. METHODS AND RESULTS: C57BL/6 mice were infected with Tc, and at the end of acute parasitemia (i.e. 45 days post-infection), treated with sildenafil (SIL, 1 mg/kg) twice per week for 3 weeks...
June 2016: JACC. Basic to Translational Science
Atchara Phumee, Apiwat Tawatsin, Usavadee Thavara, Theerakamol Pengsakul, Suwich Thammapalo, Jérôme Depaquit, Frédérick Gay, Padet Siriyasatien
Although female sand flies are best known as the vectors of Leishmania parasites and viruses, several previous reports have demonstrated that these insects can also act as vectors for the trypanosomes of bats, lizards, and snakes. In this report, we created an inventory of Phlebotomine sand flies from southern Thailand. A novel trypanosome was found in a specimen of Phlebotomus stantoni, and two sand fly species newly recorded in the country, Sergentomyia khawi and Sergentomyia hivernus, were described. PCR primer pairs specific for the internal transcribed spacer 1 (ITS1) and the small subunit ribosomal DNA (SSU rDNA) gene of trypanosomatids were used to demonstrate the presence of the parasite in the sand fly...
October 15, 2016: Journal of Medical Entomology
Lional Rajappa-Titu, Takuma Suematsu, Paola Munoz-Tello, Marius Long, Özlem Demir, Kevin J Cheng, Jason R Stagno, Hartmut Luecke, Rommie E Amaro, Inna Aphasizheva, Ruslan Aphasizhev, Stéphane Thore
Terminal uridyltransferases (TUTases) execute 3' RNA uridylation across protists, fungi, metazoan and plant species. Uridylation plays a particularly prominent role in RNA processing pathways of kinetoplastid protists typified by the causative agent of African sleeping sickness, Trypanosoma brucei In mitochondria of this pathogen, most mRNAs are internally modified by U-insertion/deletion editing while guide RNAs and rRNAs are U-tailed. The founding member of TUTase family, RNA editing TUTase 1 (RET1), functions as a subunit of the 3' processome in uridylation of gRNA precursors and mature guide RNAs...
October 15, 2016: Nucleic Acids Research
Stefan Mogk, Christian M Boßelmann, Celestin N Mudogo, Jasmin Stein, Hartwig Wolburg, Michael Duszenko
African trypanosomes induce sleeping sickness. The parasites are transmitted during the blood meal of a tsetse fly and appear primarily in blood and lymph vessels, before they enter the central nervous system. During the latter stage, trypanosomes induce a deregulation of sleep-wake cycles and some additional neurological disorders. Historically, it was assumed that trypanosomes cross the blood-brain barrier and settle somewhere between the brain cells. The brain, however, is a strictly controlled and immune-privileged area that is completely surrounded by a dense barrier that covers the blood vessels: this is the blood-brain barrier...
October 14, 2016: Biological Reviews of the Cambridge Philosophical Society
Christopher A Seid, Kathryn M Jones, Jeroen Pollet, Brian Keegan, Elissa Hudspeth, Molly Hammond, Junfei Wei, C Patrick McAtee, Leroy Versteeg, Amanda Gutierrez, Zhuyun Liu, Bin Zhan, Jonathan L Respress, Ulrich Strych, Maria Elena Bottazzi, Peter J Hotez
A therapeutic vaccine for human Chagas disease is under development by the Sabin Vaccine Institute Product Development Partnership. The aim of the vaccine is to significantly reduce the parasite burden of Trypanosoma cruzi in humans, either as a standalone product or in combination with conventional chemotherapy. Vaccination of mice with Tc24 formulated with monophosphoryl-lipid A (MPLA) adjuvant results in a Th1 skewed immune response with elevated IgG2a and IFNγ levels and a statistically significant decrease in parasitemia following T...
October 13, 2016: Human Vaccines & Immunotherapeutics
Paula Regina Elias, Gleicekelly Silva Coelho, Viviane Flores Xavier, Policarpo Ademar Sales Junior, Alvaro José Romanha, Silvane Maria Fonseca Murta, Claudia Martins Carneiro, Nilton Soares Camilo, Flaviane Francisco Hilário, Jason Guy Taylor
A series of novel xylitan derivatives derived from xylitol were synthesized using operationally simple procedures. A xylitan acetonide was the key intermediate used to prepare benzoate, arylsulfonate esters and 1,2,3-triazole derivatives of xylitan. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as positive control against T. cruzi and cytotoxicity was determined in mammalian L929 cells...
October 10, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Cher-Pheng Ooi, Sarah Schuster, Christelle Cren-Travaillé, Eloise Bertiaux, Alain Cosson, Sophie Goyard, Sylvie Perrot, Brice Rotureau
Trypanosoma vivax is the most prevalent trypanosome species in African cattle. It is thought to be transmitted by tsetse flies after cyclical development restricted to the vector mouthparts. Here, we investigated the kinetics of T. vivax development in Glossina morsitans morsitans by serial dissections over 1 week to reveal differentiation and proliferation stages. After 3 days, stable numbers of attached epimastigotes were seen proliferating by symmetric division in the cibarium and proboscis, consistent with colonization and maintenance of a parasite population for the remaining lifespan of the tsetse fly...
2016: Frontiers in Cellular and Infection Microbiology
Jose A Garcia-Salcedo, Juan D Unciti-Broceta, Javier Valverde-Pozo, Miguel Soriano
Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects...
2016: Frontiers in Pharmacology
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