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zinc t cruzi

R C Dietrich, L N Alberca, M D Ruiz, P H Palestro, C Carrillo, A Talevi, L Gavernet
Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old drugs, benznidazole and nifurtimox, which have restricted efficacy against the chronic phase of the illness. To overcome the lack of efficacy of the traditional drugs (and their considerable toxicity), new molecular targets have been studied as starting points to the discovery of new antichagasic compounds. Among them, polyamine transporter TcPAT12 (also known as TcPOT1.1) represents an interesting macromolecule, since polyamines are essential for Trypanosoma cruzi, the parasite that causes the illness, but it cannot synthesize them de novo...
April 10, 2018: European Journal of Medicinal Chemistry
Monica Visnieski Alcantara, Rafael Luis Kessler, Rosana Elisa Gonçalves Gonçalves, Newmar Pinto Marliére, Alessandra Aparecida Guarneri, Gisele Fernanda Assine Picchi, Stenio Perdigão Fragoso
In the protozoan parasite Trypanosoma cruzi - the causative agent of Chagas disease - gene expression control is mainly post-transcriptional, where RNA-binding proteins (RBPs) play a central role, by controlling mRNA stability, distribution and translation. A large variety of RBPs are encoded in the T. cruzi genome, including the CCCH-type zinc finger (CCCH ZnF) protein family, which is characterized by the presence of the C-X7/8 -C-X5 -C-X3 -H (CCCH) motif. In the related parasite T. brucei, CCCH ZnF proteins have been shown to control key differentiation steps in the parasite's life cycle...
April 2018: Molecular and Biochemical Parasitology
Laís Pessanha de Carvalho, Edésio José Tenório de Melo
Trypanosoma cruzi has many molecules that need metallic elements to work, allowing cell invasion and the establishment of infection, causing Chagas disease. Nonetheless, knowledge regarding how the parasites address metals and maintain homeostasis is lacking. To study this relationship, zinc, cadmium and mercury were chosen. Epimastigote, trypomastigote and intracellular forms of T. cruzi were incubated with these metals for different times and at different concentrations. In general, epimastigotes were the most sensitive and trypomastigotes the most resistant to metals...
October 28, 2017: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Cássia Mariana Bronzon da Costa, Marina Del Vecchio Filipin, Fabrícia Helena Santello, Luiz Miguel Pereira, Miriam Paula Alonso Toldo, José Clóvis do Prado Júnior, Ana Amélia Carraro Abrahão
Chagas disease afflicts 7 to 8 million people worldwide and congenital Chagas' disease usually leads to changes in the maternal environment, culminating in fetal adaptations. Several articles have described the importance of micronutrients on pregnancy, which is sensitive to infections. In Trypanosoma cruzi endemic regions, the Chagas disease is aggravated by the lack of micronutrients in an average diet, to which pregnant women are more susceptible. The aim of this study was to evaluate distinct T cells phenotypes and intracellular cytokines by flow cytometry in pregnant Wistar rats under zinc therapy during experimental Chagas' disease...
October 12, 2017: European Journal of Pharmaceutical Sciences
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
Gabriela Assis Burle-Caldas, Viviane Grazielle-Silva, Melissa Soares-Simões, Gabriela Schumann Burkard, Isabel Roditi, Wanderson Duarte DaRocha, Santuza M Teixeira
Gene function studies in Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, have been hindered by the lack of efficient genetic manipulation protocols. In most organisms, insertion and deletion of DNA fragments in the genome are dependent on the generation of double-stranded DNA break (DSB) and repair. By inducing a site-specific DSB, zinc finger nucleases (ZFNs) have proven to be useful to enhance gene editing in many cell types. Using a pair of ZFNs targeted to the T. cruzi gp72 gene, we were able to generate gp72 knockout parasites with improved efficiency compared to the conventional gene knockout protocol...
March 2017: Molecular and Biochemical Parasitology
Vânia Brazão, Fabricia Helena Santello, Marina Del Vecchio Filipin, Angela Palamin Azevedo, Míriam Paula Alonso Toldo, Fabiana Rossetto de Morais, José Clóvis do Prado
After one century of the discovery of Chagas' disease and the development of an efficient drug with amplitude of actions both in the acute and chronic phase is still a challenge. Alternative immune modulators have been exhaustively used. For that purpose, melatonin and zinc were administered during chronic Trypanosoma cruzi-infected Wistar rats and several endpoints were assessed. Melatonin has a remarkable functional versatility, being associated with important antioxidant, anti-inflammatory, and anti-apoptotic effects...
March 2015: Journal of Pineal Research
Vânia Brazão, Marina Del Vecchio Filipin, Fabricia Helena Santello, Angela Palamin Azevedo, Míriam Paula Alonso Toldo, Fabiana Rossetto de Morais, José Clóvis do Prado
The immunomodulatory effects of melatonin and zinc during chronic experimental Chagas' disease were studied. Early and late apoptosis by Annexin V-propidium iodide staining were evaluated. The expression of CD28, CD80, CD86, CD45RA and CD4(+)T and CD8(+)T cells were also evaluated by flow cytometry analysis. The combination of zinc and melatonin notably reduced the apoptotic ratios of splenic cells in the infected and treated animals when compared to untreated rats, during early and late stages of apoptosis...
May 2015: Immunobiology
Lysangela Ronalte Alves, Camila Oliveira, Patrícia Alves Mörking, Rafael Luis Kessler, Sharon Toledo Martins, Bruno Accioly Alves Romagnoli, Fabricio Kerrynton Marchini, Samuel Goldenberg
Trypanosome gene expression is regulated almost exclusively at the posttranscriptional level, through mRNA stability, storage and degradation. Here, we characterize the ribonucleoprotein complex (mRNPs) corresponding to the zinc finger protein TcZC3H39 from T. cruzi comparing cells growing in normal conditions and under nutritional stress. The nutritional stress is a key step during T. cruzi differentiation from epimastigote form to human infective metacyclic trypomastigote form. The mechanisms by which the stress, altogether with other stimuli, triggers differentiation is not well understood...
2014: RNA Biology
Fredy R S Gutierrez, Wander R Pavanelli, Tiago S Medina, Grace K Silva, Flávia S Mariano, Paulo M M Guedes, Tiago W P Mineo, Marcos A Rossi, Fernando Q Cunha, João S Silva
The infection with Trypanosoma cruzi induces a robust cardiac inflammation that plays a pathogenic role in the development of Chagas heart disease. In this study, we aimed at investigating the effects of Haem Oxygenase (HO) during experimental infection by T. cruzi in BALB/c and C57BL/6 mice. HO has recently emerged as a key factor modulating the immune response in diverse models of inflammatory diseases. In mice with two different genetic backgrounds, the pharmacologic inhibition of HO activity with zinc-protoporphyrin IX (ZnPPIX) induced enhanced myocarditis and reduced parasitaemia, which was accompanied by an amplified production of nitric oxide and increased influx of CD4(+), CD8(+) and IFN-γ(+) cells to the myocardium in comparison with the control group...
January 2014: Microbes and Infection
Bill R Miller, Adrian E Roitberg
Chagas' is a fatal disease that affects millions of people worldwide. The lack of safe and effective treatments for Chagas' highlights the need for the discovery of new drugs to fight the disease. Trypanosoma cruzi, the parasitic cause of Chagas' disease, synthesizes a trans-sialidase (TcTS) enzyme responsible for the transfer of sialic acids from the host cell surface to glycoconjugates on the parasitic cell surface. TcTS has no human analogs and is vital to the life cycle of T. cruzi, making TcTS an important enzyme for drug design against Chagas' disease...
September 2013: Journal of Molecular Graphics & Modelling
Helton J Wiggers, Josmar R Rocha, William B Fernandes, Renata Sesti-Costa, Zumira A Carneiro, Juliana Cheleski, Albérico B F da Silva, Luiz Juliano, Maria H S Cezari, João S Silva, James H McKerrow, Carlos A Montanari
A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies...
2013: PLoS Neglected Tropical Diseases
Peiwen Pan, Alane Beatriz Vermelho, Andrea Scozzafava, Seppo Parkkila, Clemente Capasso, Claudiu T Supuran
The protozoan pathogen Trypanosoma cruzi, the causative agent of Chagas disease, encodes an α-class carbonic anhydrase (CA, EC, TcCA, which was recently shown to be crucial for its life cycle. Thiols, a class of strong TcCA inhibitors, were also shown to block the growth of the pathogen in vitro. Here we report the inhibition of TcCA by inorganic and complex anions and other molecules interacting with zinc proteins, such as sulfamide, sulfamic acid, phenylboronic/arsonic acids. TcCA was inhibited in the low micromolar range by iodide, cyanate, thiocyanate, hydrogensulfide and trithiocarbonate (KIs in the range of 44-93 μM), but the best inhibitor was diethyldithiocarbamate (KI=5 μM)...
August 1, 2013: Bioorganic & Medicinal Chemistry
Paulo H M Calixto, Mainá Bitar, Keila A M Ferreira, Odonírio Abrahão, Eliane Lages-Silva, Glória R Franco, Luis E Ramírez, André L Pedrosa
Trypanosoma rangeli is a hemoflagellate parasite which is able to infect humans. Distinct from Trypanosoma cruzi, the causative agent of Chagas disease, T. rangeli is non-pathogenic to the vertebrate host. The manner by which the T. rangeli interacts with the host is still unknown, but it certainly depends on the surface molecules. Major surface proteins (MSP) are GPI-anchored, zinc-dependent metalloproteases present in the surface of all trypanosomatids studied so far, which are implicated as virulence factors in pathogenic trypanosomatids, such as Leishmania spp and T...
August 2013: Journal of Molecular Modeling
Patricia Alves Mörking, Rita de Cássia Pontello Rampazzo, Pegine Walrad, Christian Macagnan Probst, Maurilio José Soares, Daniela Fiori Gradia, Daniela Parada Pavoni, Marco Aurélio Krieger, Keith Matthews, Samuel Goldenberg, Stenio Perdigão Fragoso, Bruno Dallagiovanna
Trypanosomes are parasitic protozoa in which gene expression is primarily controlled through the regulation of mRNA stability and translation. This post-transcriptional control is mediated by various families of RNA-binding proteins, including those with zinc finger CCCH motifs. CCCH zinc finger proteins have been shown to be essential to differentiation events in trypanosomatid parasites. Here, we functionally characterise TcZFP2 as a predicted post-transcriptional regulator of differentiation in Trypanosoma cruzi...
September 2012: Memórias do Instituto Oswaldo Cruz
Vânia Brazão, Marina Del Vecchio Filipin, Fabricia Helena Santello, Leony Cristina Caetano, Ana Amélia Carraro Abrahão, Míriam Paula Alonso Toldo, José Clóvis do Prado
Melatonin by exhibiting antioxidant, anti-aging, and immunomodulatory properties favorably modulate the immune function, protecting the hosts from several infectious diseases. Zinc is an essential trace element important for the efficiency of the immune system in reason of its widespread role in the activity of enzymes, transcription factors and cytokines. The etiology of Chagas' disease, caused by a protozoan parasite Trypanosoma cruzi, has been the focus of considerable discussion, although chronic phase still remains not fully understood...
December 2011: Cytokine
Gabriela Niemirowicz, Daniel Fernández, Maria Solà, Juan J Cazzulo, Francesc X Avilés, F Xavier Gomis-Rüth
Trypanosoma cruzi is the aetiological agent of Chagas' disease, a chronic infection that affects millions in Central and South America. Proteolytic enzymes are involved in the development and progression of this disease and two metallocarboxypeptidases, isolated from T. cruzi CL Brener clone, have recently been characterized: TcMCP-1 and TcMCP-2. Although both are cytosolic and closely related in sequence, they display different temporary expression patterns and substrate preferences. TcMCP-1 removes basic C-terminal residues, whereas TcMCP-2 prefers hydrophobic/aromatic residues...
November 2008: Molecular Microbiology
Raquel Elisa da Silva-Lopez, José Andrés Morgado-Díaz, Priscila Tavares dos Santos, Salvatore Giovanni-De-Simone
An extracellular serine peptidase was purified 460-fold from Trypanosoma cruzi epimastigotes culture supernatant with (NH(4))(2)SO(4) precipitation followed by affinity chromatography aprotinin-agarose and continuous elution electrophoresis, yielding a total recovery of 65%. The molecular mass of the active enzyme estimated by reducing and non-reducing SDS-PAGE was about 75kDa. The optimal pH and temperature of this glycosylated peptidase were 8.0 and 37 degrees C using alpha-N-rho-tosyl-L-arginine-methyl ester (L-TAME) as substrate...
August 2008: Acta Tropica
Vânia Brazão, Leony Cristina Caetano, Marina Del Vecchio Filipin, Miriam Paula Alonso Toldo, Luana Naiara Caetano, José Clóvis do Prado
It is well recognized that zinc is an essential trace element for all organisms, influencing growth and affecting the development and integrity of the immune system. It is also well known that the protective response against Trypanosoma cruzi depends on both innate and acquired immunity and for the control of the parasite load and host survival, the participation of special cells such natural killer (NK), T and B lymphocytes and macrophages are required. So the aims of this study were to evaluate the effects of zinc supplementation on the host's immune response infected with T...
June 14, 2008: Veterinary Parasitology
Vânia Brazão, Marina Del Vecchio Filipin, Leony Cristina Caetano, Miriam Paula Alonso Toldo, Luana Naiara Caetano, José Clóvis do Prado
It is well recognized that zinc is an essential trace element, influencing growth and affecting the development and integrity of the immune system. The use of oligoelements as zinc can be considered a tool in modulating the effectiveness of the immune response. In this work zinc was daily and orally supplied in male Wistar rats infected with the Y strain of Trypanosoma cruzi. Parasitemia was evaluated and a significant reduction on blood parasites was observed. In order to check some immunological parameters peritoneal macrophages were counted revealing higher percentages for zinc supplied group...
April 2008: Experimental Parasitology
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